Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3, 165-183 (1991) and Murphy, Rev. Immun., 12, 593-633 (1994)). There are two classes of chemokines, Cxe2x80x94Xxe2x80x94C (xcex1) and Cxe2x80x94C (xcex2), depending on whether the first two cysteines are separated by a single amino acid (Cxe2x80x94Xxe2x80x94C) or are adjacent (Cxe2x80x94C). The xcex1-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas xcex2-chemokines, such as RANTES, MIP-1xcex1, MIP-1xcex2, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature, 381, 661-666 (1996)).
The chemokines bind specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed xe2x80x9cchemokine receptors.xe2x80x9d On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least sixteen human chemokine receptors that bind or respond to xcex2-chemokines with the following characteristic pattern: CCR-1 (or xe2x80x9cCKR-1xe2x80x9d or xe2x80x9cCC-CKR-1xe2x80x9d) [MIP-1xcex1, MIP-1xcex2, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem., 270, 22123-22128 (1995); Beote, et al, Cell, 72, 415-425 (1993)); CCR-2A and CCR-2B (or xe2x80x9cCKR-2Axe2x80x9d/xe2x80x9cCKR-2Axe2x80x9d or xe2x80x9cCC-CKR-2Axe2x80x9d/xe2x80x9cCC-CKR-2Axe2x80x9d) [MCP-1, MCP-3, MCP-4]; CCR-3 (or xe2x80x9cCKR-3xe2x80x9d or xe2x80x9cCC-CKR-3xe2x80x9d) [eotaxin, RANTES, MCP-3] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995); CCR-4 (or xe2x80x9cCKR-4xe2x80x9d or xe2x80x9cCC-CKR4xe2x80x9d) [MIP-1xcex1, RANTES, MCP-1] (Power, et al., J. Biol. Chem., 270, 19495-19500 (1995)); CCR-5 (or xe2x80x9cCKR-5xe2x80x9d or xe2x80x9cCC-CKR-5xe2x80x9d) [MIP-1xcex1, RANTES, MIP-1xcex2] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); and the Duffy blood-group antigen [RANTES, MCP-1] (Chaudhun, et al., J. Biol. Chem., 269, 7835-7838 (1994)). The xcex2-chemokines include eotaxin, MIP (xe2x80x9cmacrophage inflammatory proteins), MCP (xe2x80x9cmonocyte chemoattractant proteinxe2x80x9d) and RANTES (xe2x80x9cregulation-upon-activation, normal T expressed and secretedxe2x80x9d).
Chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. A review of the role of chemokines in allergic inflammation is provided by Kita, H., et al., J. Exp. Med. 183, 2421-2426 (1996). Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. Compounds which modulate chemokine receptors would be especially useful in the treatment and prevention of atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and particularly bronchial asthma.
A retrovirus designated human immunodeficiency virus (HIV-1) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV.
Certain compounds have been demonstrated to inhibit the replication of HIV, including soluble CD4 protein and synthetic derivatives (Smith, et al., Science, 238, 1704-1707 (1987)), dextran sulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes (U.S. Pat. No. 5,468,469). Some of these antiviral agents have been shown to act by blocking the binding of gp120, the coat protein of HIV, to its target, the CD4 glycoprotein of the cell.
Entry of HIV-1 into a target cell requires cell-surface CD4 and additional host cell cofactors. Fusin has been identified as a cofactor required for infection with virus adapted for growth in transformed T-cells, however, fusin does not promote entry of macrophagetropic viruses which are believed to be the key pathogenic strains of HIV in vivo. It has recently been recognized that for efficient entry into target cells, human immunodeficiency viruses require a chemokine receptors, most probably CCR-5 or CXCR-4, as well as the primary receptor CD4 (Levy, N. Engl. J. Med., 335(20), 1528-1530 (Nov. 14, 1996). The principal cofactor for entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HIV-1 is CCR5, a receptor for the xcex2-chemokines RANTES, MIP-1xcex1 and MIP-1xcex2 (Deng, et al., Nature, 381, 661-666 (1996)). HIV attaches to the CD4 molecule on cells through a region of its envelope protein, gp120, It is believed that the CD-4 binding site on the gp120 of HIV interacts with the CD4 molecule on the cell surface, and undergoes conformational changes which allow it to bind to another cell-surface receptor, such as CCR5 and/or CXCR-4. This brings the viral envelope closer to the cell surface and allows interaction between gp41 on the viral envelope and a fusion domain on the cell surface, fusion with the cell membrane, and entry of the viral core into the cell. It has been shown that xcex2-chemokine ligands prevent HIV-1 from fusing with the cell (Dragic, et al., Nature, 381, 667-673 (1996)). It has further been demonstrated that a complex of gp120 and soluble CD4 interacts specifically with CCR-5 and inhibits the binding of the natural CCR-5 ligands MIP-1xcex1 and MIP-1xcex2 (Wu, et al., Nature, 384, 179-183 (1996); Trkola, et al., Nature, 384, 184-187 (1996)).
Humans who are homozygous for mutant CCR-5 receptors which do not serve as co-receptors for HIV-1 in vitro appear to be unusually resistant to HIV-1 infection and are not immuno-compromised by the presence of this genetic variant (Nature, 382, 722-725 (1996)). Absence of CCR-5 appears to confer substantial protection from HIV-1 infection (Nature, 382, 668-669 (1996)). Other chemokine receptors may be used by some strains of HIV-1 or may be favored by non-sexual routes of transmission. Although most HIV-1 isolates studied to date utilize CCR-5 or fusin, some can use both as well as the related CCR-2B and CCR-3 as co-receptors (Nature Medicine, 2(11), 1240-1243 (1996)). Nevertheless, drugs targeting chemokine receptors may not be unduly compromised by the genetic diversity of HIV-1 (Zhang, et al., Nature, 383, 768 (1996)). Accordingly, an agent which could block chemokine receptors in humans who possess normal chemokine receptors should prevent infection in healthy individuals and slow or halt viral progression in infected patients. By focusing on the host""s cellular immune response to HIV infection, better therapies towards all subtypes of HIV may be provided. These results indicate that inhibition of chemokine receptors presents a viable method for the prevention or treatment of infection by HIV and the prevention or treatment of AIDS.
The peptides eotaxin, RANTES, MIP-1xcex1, MIP-1xcex2, MCP-1, and MCP-3 are known to bind to chemokine receptors. As noted above, the inhibitors of HIV-1 replication present in supernatants of CD8+ T cells have been characterized as the xcex2-chemokines RANTES, MIP-1xcex1 and MIP-1xcex2.
The present invention is directed to compounds which inhibit the entry of human immunodeficiency virus (HIV) into target cells and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the prevention and/or treatment of the resulting acquired immune deficiency syndrome (AIDS). The present invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the prevention and treatment of AIDS and viral infection by HIV.
The present invention is further directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
The present invention is directed to compounds of formula I: 
wherein:
X is selected from:
xe2x80x94(C0-6 alkyl)-Yxe2x80x94(C0-6 alkyl)-, xe2x80x94(C0-6 alkyl)-C3-8 cycloalkyl-(C0-6 alkyl)-, C2-10 alkenyl, and C2-10 alkynyl,
where the alkyl is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) xe2x80x94Oxe2x80x94C1-3 alkyl, and
(d) trifluoromethyl,
and where Y is selected from:
a single bond, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94SO2xe2x80x94, xe2x80x94SO2xe2x80x94NR10xe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94SOxe2x80x94,
and where R10 is independently selected from: hydrogen, C1-6 alkyl, benzyl, phenyl, and C1-6 alkyl-C3-6 cycloalkyl,
which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl;
R1 is selected from:
(1) xe2x80x94CO2H,
(2) xe2x80x94NO2,
(3) -tetrazolyl,
(4) -hydroxyisoxazole,
(5) xe2x80x94SO2NHCOxe2x80x94(C0-3 alkyl)-R9, wherein R9 is independently selected from: hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl, and
(6) xe2x80x94P(O)(OH)2;
R3 is selected from the group consisting of:
phenyl and heterocycle,
which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) xe2x80x94Oxe2x80x94C1-3 alkyl,
(f) xe2x80x94CO2R9,
(g) xe2x80x94NR9R10, and
(h) xe2x80x94CONR9R10;
R4, R5 and R6 are independently selected from:
hydrogen, C1-10 alkyl, C3-8 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, phenyl, xe2x80x94(C1-6 alkyl)-phenyl, xe2x80x94(C1-6 alkyl)-C3-8 cycloalkyl, naphthyl, biphenyl, and heterocycle,
which is unsubstituted or substituted with 1-7 of R11 where R11 is independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) xe2x80x94Oxe2x80x94C1-3 alkyl,
(f) xe2x80x94CO2R9,
(g) xe2x80x94NR9R10, and
(h) xe2x80x94CONR9R10,
or where R4 and R5 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11,
or where R5 and R6 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11;
R7 is selected from:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from: hydroxy, cyano, and halo,
(3) hydroxy, and
(4) halo;
R8 is selected from:
hydrogen, C3-8 cycloalkyl, phenyl, naphthyl, biphenyl, and heterocycle,
which is unsubstituted or substituted with 1-7 of R12 where R12 is independently selected from:
(a) halo,
(b) cyano,
(c) hydroxy,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13 where R13 is independently selected from: halo, cyano, hydroxy, C1-6 alkoxy, xe2x80x94CO2H, xe2x80x94CO2(C1-6 alkyl), trifluoromethyl, and xe2x80x94NR9R10,
(e) xe2x80x94Oxe2x80x94C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13,
(f) xe2x80x94CF3,
(g) xe2x80x94CHF2,
(h) xe2x80x94CH2F,
(i) xe2x80x94NO2,
(j) C0-6 alkyl-phenyl or C0-6 alkyl-heterocycle, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(i) halo,
(ii) hydroxy,
(iii) C1-6 alkyl, unsubstituted or substituted with 1-5 substituents, each of which is independently selected from halo, cyano, hydroxy, C1-6 alkoxy, xe2x80x94CO2H, xe2x80x94CO2(C1-6 alkyl), trifluoromethyl, and xe2x80x94NR9R10,
(iv) xe2x80x94Oxe2x80x94C1-6 alkyl,
(v) xe2x80x94CF3,
(vi) xe2x80x94OCF3,
(vii) xe2x80x94NO2,
(viii) xe2x80x94CN,
(ix) xe2x80x94SO2xe2x80x94C1-6 alkyl,
(x) xe2x80x94CO2R9,
(xi) xe2x80x94NR9R10,
(xii) xe2x80x94CONR9R10,
(xiii) xe2x80x94SO2xe2x80x94NR9R10,
(xiv) xe2x80x94NR9xe2x80x94SO2xe2x80x94R10,
(xv) xe2x80x94C3-8 cycloalkyl,
(xvi) xe2x80x94OC3-8 cycloalkyl, and
(xvii) phenyl;
(k) xe2x80x94CO2R9,
(l) tetrazolyl,
(m) xe2x80x94NR9R10,
(n) xe2x80x94NR9xe2x80x94COR10,
(o) xe2x80x94NR9xe2x80x94CO2R10,
(p) xe2x80x94COxe2x80x94NR9R10,
(q) xe2x80x94OCOxe2x80x94NR9R10,
(r) xe2x80x94NR9COxe2x80x94NR9R10,
(s) xe2x80x94S(O)mxe2x80x94R9,wherein m is an integer selected from 0, 1 and 2,
(t) xe2x80x94S(O)2xe2x80x94NR9R10,
(u) xe2x80x94NR9S(O)2xe2x80x94R10,
(v) xe2x80x94NR9S(O)2xe2x80x94NR9R10,
(w) C1-6 alkyl substituted with xe2x80x94C3-8 cycloalkyl, and
(x) xe2x80x94C3-8 cycloalkyl;
n is an integer selected from 1, 2, 3 and 4;
x is an integer selected from 0, 1 and 2, and y is an integer selected from 0, 1 and 2, with the proviso that the sum of x and y is 2;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
In one embodiment, the present invention is directed to compounds of Formula I, and pharmaceutically acceptable salts thereof and individual diastereomers thereof, wherein
R1 is selected from:
(1) xe2x80x94CO2H,
(2) xe2x80x94NO2,
(3) -tetrazolyl,
(4) -hydroxyisoxazole, and
(5) xe2x80x94P(O)(OH)2;
R8 is selected from:
hydrogen, C3-8 cycloalkyl, phenyl, naphthyl, biphenyl, and heterocycle,
which is unsubstituted or substituted with 1-7 of R12 where R12 is independently selected from:
(a) halo,
(b) cyano,
(c) hydroxy,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13 where R13 is independently selected from: halo, cyano, hydroxy, C1-6 alkoxy, xe2x80x94CO2H, xe2x80x94CO2(C1-6 alkyl), trifluoromethyl, and xe2x80x94NR9R10,
(e) xe2x80x94Oxe2x80x94C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13,
(f) xe2x80x94CF3,
(g) xe2x80x94CHF2,
(h) xe2x80x94CH2F,
(i) xe2x80x94NO2,
(j) C0-6 alkyl-phenyl or C0-6 alkyl-heterocycle, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(i) halo,
(ii) hydroxy,
(iii) C1-6 alkyl,
(iv) xe2x80x94Oxe2x80x94C1-6 alkyl,
(v) xe2x80x94CF3,
(vi) xe2x80x94OCF3,
(vii) xe2x80x94NO2,
(viii) xe2x80x94CN,
(ix) xe2x80x94SO2xe2x80x94C1-6 alkyl,
(x) xe2x80x94CO2R9,
(xi) xe2x80x94NR9R10,
(xii) xe2x80x94CONR9R10,
(xiii) xe2x80x94SO2xe2x80x94NR9R10, and
(xiv) xe2x80x94NR9xe2x80x94SO2xe2x80x94R10;
(k) xe2x80x94CO2R9,
(l) tetrazolyl,
(m) xe2x80x94NR9R10,
(n) xe2x80x94NR9xe2x80x94COR10,
(o) xe2x80x94NR9xe2x80x94CO2R10,
(p) xe2x80x94COxe2x80x94NR9R10,
(q) xe2x80x94OCOxe2x80x94NR9R10,
(r) xe2x80x94NR9COxe2x80x94NR9R10,
(s) xe2x80x94S(O)mxe2x80x94R9,wherein m is an integer selected from 0, 1 and 2,
(t) xe2x80x94S(O)2xe2x80x94NR9R10,
(u) xe2x80x94NR9S(O)2xe2x80x94R10, and
(v) xe2x80x94NR9S(O)2xe2x80x94NR9R10;
and all else is as defined above.
Preferred compounds of the present invention include those of formula Ia: 
wherein R1, R3, R4, R5, R6, R7, R8, X and n are defined herein;
and pharmaceutically acceptable salts and individual diastereomers thereof.
More preferred compounds of the present invention include those of formula Ic: 
wherein R1, R3, R4, R5, R6, R7, R8 and X are defined herein;
and pharmaceutically acceptable salts and individual diastereomers thereof.
Highly preferred compounds of the present invention include those of formula Id: 
wherein R3, R4, R5, R6, R8 and X are defined herein;
and pharmaceutically acceptable salts and individual diastereomers thereof.
More highly preferred compounds of the present invention include those of formula Ie: 
wherein R4, R5, R6, R8 and X are defined herein;
and pharmaceutically acceptable salts and individual diastereomers thereof.
In the present invention it is preferred that R1 is selected from:
(1) xe2x80x94CO2H,
(2) xe2x80x94P(O)(OH)2, and
(3) -tetrazolyl.
In the present invention it is more preferred that R1 is selected from:
(1) xe2x80x94CO2H, and
(2) -tetrazolyl.
In the present invention it is even more preferred that R1 is xe2x80x94CO2H.
In the present invention it is preferred that R3 is selected from the group consisting of:
phenyl and thienyl,
which may be unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl, and
(e) xe2x80x94Oxe2x80x94C1-3 alkyl.
In the present invention it is more preferred that R3 is selected from the group consisting of:
phenyl and thienyl,
which may be unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) fluoro,
(b) chloro,
(c) trifluoromethyl,
(d) hydroxy, and
(e) C1-3 alkyl.
In the present invention it is even more preferred that R3 is selected from the group consisting of:
phenyl, which may be unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) fluoro, and
(b) chloro; and
unsubstituted thienyl.
In the present invention it is still more preferred that R3 is unsubstituted phenyl, (3-fluoro)phenyl or 3-thienyl.
In the present invention it is preferred that R4 is hydrogen or C1-6 alkyl.
In the present invention it is more preferred that R4 is hydrogen.
In the present invention it is preferred that R5 is selected from: hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkyl-C3-8 cycloalkyl, and phenyl.
In the present invention it is more preferred that R5 is selected from: hydrogen, methyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, and phenyl.
In the present invention it is still more preferred that R5 is selected from: isopropyl, isobutyl, sec-butyl, and cyclohexyl.
In the present invention it is preferred that R6 is selected from: hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkyl-C3-8 cycloalkyl, and phenyl.
In the present invention it is more preferred that R6 is selected from: hydrogen, methyl, n-butyl, t-butyl, isobutyl, sec-butyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, and cyclohexyl.
In the present invention it is still more preferred that R6 is selected from: hydrogen, methyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, and cyclohexyl.
In an alternate embodiment of the present invention it is preferred that R5 and R6 are joined together to form a C3-8 cycloalkyl ring.
In an alternate embodiment of the present invention it is more preferred that R5 and R6 are joined together to form a pyrrolidine ring.
In another alternate embodiment of the present invention it is more preferred that R4 and R5 are joined together to form a C3-8 cycloalkyl ring. In an aspect of this embodiment, the ring formed by joining R4 and R5 is cyclopentyl.
In the present invention it is preferred that R7 is hydrogen, fluoro, hydroxy or C1-6 alkyl.
In the present invention it is more preferred that R7 is hydrogen or fluoro.
In the present invention it is even more preferred that R7 is hydrogen.
In the present invention it is preferred that X is:
xe2x80x94(C0-4 alkyl)-Yxe2x80x94(C0-4 alkyl)xe2x80x94,
where the alkyl is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) xe2x80x94Oxe2x80x94C1-3 alkyl, and
(d) trifluoromethyl,
and where Y is selected from:
a single bond, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94SOxe2x80x94,
and where R10 is independently selected from:
hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, benzyl, phenyl, and C1-6 alkyl-C3-6 cycloalkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl.
In the present invention it is more preferred that X is:
xe2x80x94(C0-2 alkyl)-Yxe2x80x94(C0-2 alkyl)-,
where the alkyl is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) xe2x80x94Oxe2x80x94C1-3 alkyl, and
(d) trifluoromethyl,
and where Y is selected from:
a single bond, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94SOxe2x80x94,
where R10 is independently selected from:
hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, benzyl, phenyl, and C1-6 alkyl-C3-6 cycloalkyl,
which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl.
In the present invention it is even more preferred that X is selected from:
xe2x80x94(C0-2 alkyl)-Yxe2x80x94(C0-2 alkyl)-, where the alkyl is unsubstituted or substituted with fluoro,
and where Y is selected from:
a single bond, xe2x80x94SO2xe2x80x94, xe2x80x94SOxe2x80x94, and xe2x80x94NR10xe2x80x94,
where R10 is independently selected from: hydrogen, C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl.
In the present invention it is still more preferred that X is selected from:
(1) a single bond,
(2) xe2x80x94CH2CH2xe2x80x94,
(3) xe2x80x94CH2CH2CH2xe2x80x94,
(4) xe2x80x94CH2CH2xe2x80x94CF2xe2x80x94,
(5) xe2x80x94CH2CH2xe2x80x94SO2xe2x80x94, and
(6) xe2x80x94CH2CH2xe2x80x94SOxe2x80x94.
In the present invention it is preferred that R8 is selected from:
phenyl, naphthyl, cyclohexyl, benzoimidazolyl, benzofurazanyl, imidazopyridyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, thiazolyl, tetrazolopyridyl, pyrazolyl, tetrahydroindazolyl, tetrahydroimidazopyridyl, and tetrahydropyrazolopyridyl;
which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) cyano,
(c) hydroxy,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13 where R13 is independently selected from: halo, cyano, hydroxy, C1-6 alkoxy, xe2x80x94CO2H, xe2x80x94CO2(C1-6 alkyl), trifluoromethyl, and xe2x80x94NR9R10, wherein R9 and R10 are independently selected from: hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl;
(e) xe2x80x94Oxe2x80x94C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13,
(f) xe2x80x94CF3,
(g) xe2x80x94CHF2,
(h) xe2x80x94CH2F,
(i) xe2x80x94NO2,
(j) C0-6 alkyl-phenyl or C0-6 alkyl-heterocycle, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(i) halo,
(ii) hydroxy,
(iii) C1-6 alkyl,
(iv) xe2x80x94Oxe2x80x94C1-6 alkyl,
(v) xe2x80x94CF3,
(vi) xe2x80x94OCF3,
(vii) xe2x80x94NO2,
(viii) xe2x80x94CN,
(ix) xe2x80x94SO2xe2x80x94C1-6 alkyl,
(x) xe2x80x94CO2R9,
(xi) xe2x80x94NR9R10,
(xii) xe2x80x94CONR9R10,
(xiii) xe2x80x94SO2xe2x80x94NR9R10, and
(xiv) xe2x80x94NR9xe2x80x94SO2xe2x80x94R10;
(k) xe2x80x94CO2R9,
(l) tetrazolyl,
(m) xe2x80x94NR9R10,
(n) xe2x80x94NR9xe2x80x94COR10,
(o) xe2x80x94NR9xe2x80x94CO2R10,
(p) xe2x80x94COxe2x80x94NR9R10,
(q) xe2x80x94OCOxe2x80x94NR9R10,
(r) xe2x80x94NR9COxe2x80x94NR9R10,
(s) xe2x80x94S(O)mxe2x80x94R9,wherein m is an integer selected from 0, 1 and
(t) xe2x80x94S(O)2xe2x80x94NR9R10,
(u) xe2x80x94NR9S(O)2xe2x80x94R10, and
(v) xe2x80x94NR9S(O)2xe2x80x94NR9R10.
In an aspect of the preceding embodiment, in the present invention it is preferred that R8 is selected from: phenyl, naphthyl, cyclohexyl, benzoimidazolyl, benzofurazanyl, imidazopyridyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, thiazolyl, and tetrazolopyridyl; which is unsubstituted or substituted with 1-7 substituents as set forth in the preceding paragraph.
In the present invention it is more preferred that R8 is selected from:
phenyl, imidazopyridyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, thiazolyl, tetrahydroindazolyl, tetrahydroimidazopyridyl, and tetrahydropyrazolopyridyl;
which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) halo,
(b) cyano,
(c) xe2x80x94NO2,
(d) xe2x80x94CF3,
(e) xe2x80x94CHF2,
(f) xe2x80x94CH2F,
(h) C1-6 alkyl,
(i) C1-3 alkyl-phenyl or C1-3 alkyl-pyridyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from:
(i) halo,
(ii) C1-6 alkyl,
(iii) xe2x80x94Oxe2x80x94C1-6 alkyl,
(iv) xe2x80x94CF3,
(vi) xe2x80x94OCF3,
(vii) xe2x80x94CN, and
(j) xe2x80x94Oxe2x80x94C1-6 alkyl.
In an aspect of the preceding embodiment, in the present invention it is preferred that R8 is selected from: phenyl, imidazopyridyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, and thiazolyl; which is unsubstituted or substituted with 1-5 substituents as set forth in the preceding paragraph.
In the present invention it is even more preferred that R8 is selected from:
imidazolyl, oxazolyl, pyrazolyl, thiazolyl, tetrahydroindazolyl, tetrahydroimidazopyridyl, and tetrahydropyrazolopyridyl;
which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
(a) fluoro,
(b) cyano,
(c) C1-3 alkyl,
(d) xe2x80x94CH2-phenyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from:
(i) fluoro,
(ii) chloro,
(iii) xe2x80x94Oxe2x80x94CH3,
(iv) xe2x80x94CF3,
(v) xe2x80x94CN, and
(e) xe2x80x94CF3.
In an aspect of the preceding embodiment, in the present invention it is preferred that R8 is selected from: imidazolyl, oxazolyl, pyrazolyl, and thiazolyl; which is unsubstituted or substituted with 1-3 substituents as set forth in the preceding paragraph.
In the present invention it is still more preferred that R8 is selected from: 5-(3-benzyl)pyrazolyl, 5-(1-methyl-3-benzyl)pyrazolyl, 5-(1-ethyl-3-benzyl)pyrazolyl, 5-(2-benzyl)thiazolyl, 5-(2-benzyl-4-methyl)thiazolyl, and 5-(2-benzyl4-ethyl)thiazolyl).
In the present invention it is preferred that n is an integer selected from 1, 2 and 3.
In the present invention it is more preferred that n is an integer which is 1.
In the present invention it is preferred that x is an integer which is 1 and y is an integer which is 1.
It is to be understood that embodiments of the present invention include, but are not limited to, compounds of formula I wherein R1, R3, R4, R5, R6, R7, R8, x, y and n are defined in accordance with one of the embodiments or aspects thereof as set forth above. Any and all possible combinations of preferred, more preferred, even more preferred, highly preferred, more highly preferred, and most preferred definitions of these variables in formulas I are within the scope of the present invention.
The compounds of the instant invention have at least two asymmetric centers at the ring junction of the substitutents bearing the piperidine and R3. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The relative configurations of the more preferred compounds of this invention are of the trans orientation, i.e. as depicted: 
The relative configurations of the even more preferred compounds of this invention wherein R6 is hydrogen, methyl or wherein R5 and R6 form a pyrrolidine ring with respect to the configuration of the nitrogen substituent on the cyclopentane ring is cis to the orientation of R3 as depicted: 
The relative configurations of the most preferred compounds of this invention wherein R6 is hydrogen or methyl with respect to the configuration of the nitrogen substituent on the cyclopentane ring is is cis to the orientation of R3 and with the (R)-stereochemistry of the nitrogen side chain of the orientation as depicted: 
The relative configurations of the even more preferred compounds of this invention wherein R6 is other than hydrogen or methyl with respect to the configuration of the nitrogen substituent on the cyclopentane ring is 1,3-cis of the orientation as depicted: 
The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
In a preferred aspect the present invention is a compound of formula (II); 
R8 is selected from the group consisting of 
R12 and R14 are each independently selected from the group consisting of F, Cl, CF3, OCH3, OCH2CH3, OCF3, O-cyclobutyl, CN, O-cyclopropyl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, and SO2CH3;
G is hydrogen or fluoro; and
q is an integer equal to 1 or 2;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
As appreciated by those of skill in the art, halo or halogen as used herein are intended to include chloro, fluoro, bromo and iodo. Similarly, C1-8, as in C1-8 alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branched arrangement, such that C1-8 alkyl specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. Likewise, C0, as in C0 alkyl is defined to identify the presence of a direct covalent bond.
The term xe2x80x9cheterocyclexe2x80x9d (which may alternatively be referred to as xe2x80x9cheterocyclicxe2x80x9d) refers to a 4- to 8-membered monocyclic ring, a 7- to 11-membered bicyclic system, or a 10 to 15-membered tricyclic ring system, any ring of which is saturated or unsaturated (partially or totally), and which consists of carbon atoms and one or more heteroatoms (e.g., from 1 to 4 heteroatoms) selected from N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, the nitrogen heteroatom may optionally be quaternized, and a ring carbon may optionally be oxidized (i.e., is substituted with oxo). The heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure. A preferred heterocycle is a 4- to 8-membered monocyclic ring or a 7- to 11-membered bicyclic system, as defined and described above.
The term xe2x80x9cheterocyclexe2x80x9d as used herein is intended to include the following groups: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof.
The term xe2x80x9cheterocyclexe2x80x9d as used herein is also intended to include, but is not limited to, the following groups: methylenedioxyphenyl, imidazopyridyl, imidazopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl, imidazotriazinyl, imidazothiopheyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrazolotriazinyl, pyrazolothiophenyl, triazolopyridyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyrazinyl, triazolothiophenyl, tetrahydroimidazopyridinyl, tetrahydropyrazolopyridinyl, tetrahydrotriazopyridinyl, tetrahydrotriazolopyridazinyl, and tetrahydroindazolyl.
The term xe2x80x9cheterocyclexe2x80x9d as used herein is also intended to include, but is not limited to, the following groups: tetrahydroimidazopyrimidyl, tetrahydroimidazopyrazinyl, tetrahydroimidazopyridazinyl, tetrahydrotriazolopyrimidyl, tetrahydrotriazolopyrazinyl, tetrahydropyrazolopyrimidyl, tetrahydropyrazolopyrazinyl, imidazothiazolyl, and imidazothiadiazolyl.
The term xe2x80x9cheterocyclexe2x80x9d as used herein is also intended to include, but is not limited to, oxopyridinyl (e.g., 2-oxopyridinyl), oxopiperidinyl, and oxopyrazolyl.
The terms xe2x80x9cthiophenylxe2x80x9d and xe2x80x9cthienylxe2x80x9d have the same meaning herein and are used interchangeably. Similarly, the following pairs of terms are used interchangeably: xe2x80x9cindazolylxe2x80x9d and xe2x80x9cbenzopyrazolylxe2x80x9d; xe2x80x9cpyridinylxe2x80x9d and xe2x80x9cpyridylxe2x80x9d.
In the expression xe2x80x9c . . . which is unsubstituted or substituted with . . . xe2x80x9d, xe2x80x9cwhichxe2x80x9d is intended to refer back to all preceding chemical groups in the particular definition in which the expression appears, unless a contrary meaning is expressed or is implied by the context. Furthermore, the term xe2x80x9csubstitutedxe2x80x9d in the expression includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution is chemically allowed in any of the named chemical groups. Thus, for example, the expression xe2x80x9cis independently selected from: hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents . . . xe2x80x9d, encompasses hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl, phenyl, mono- and di- and tri-substituted C1-6 alkyl, mono- and di- and tri-substituted C5-6 cycloalkyl, mono- and di- and tri-substituted benzyl and mono- and di- and tri-substituted phenyl.
Exemplifying the invention is the use of the compounds disclosed in the Examples and herein.
Specific compounds within the present invention include a compound which is selected from the group consisting of: 
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
Specific compounds within the present invention also include compounds selected from the group consisting of: 
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
An aspect of the present invention is a compound selected from the group consisting of: 
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
Another aspect of the present invention is 
or a pharmaceutically acceptable salt thereof.
The subject compounds are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound.
The present invention is directed to the use of the foregoing compounds as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors, including CCR-5 and/or CCR3.
The utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assay for chemokine binding as disclosed by Van Riper, et al., J. Exp. Med 177 851-856 (1993) which may be readily adapted for measurement of CCR-5 binding, and the assay for CCR-3 binding as disclosed by Daugherty, et al., J. Exp. Med. 183, 2349-2354 (1996). Cell lines for expressing the receptor of interest include those naturally expressing the receptor, such as EOL-3 or THP-1, or a cell engineered to express a recombinant receptor, such as CHO, RBL-2H3, HEK-293. For example, a CCR3 transfected AML14.3D10 cell line has been placed on restricted deposit with American Type Culture Collection in Rockville, Md. as ATCC No. CRL-12079, on Apr. 5, 1996. The utility of the compounds in accordance with the present invention as inhibitors of the spread of HIV infection in cells may be demonstrated by methodology known in the art, such as the HIV quantitation assay disclosed by Nunberg, et al., J. Virology, 65 (9), 4887-4892 (1991).
In particular, the compounds of the following examples had activity in binding to the CCR-5 or the CCR-3 receptor in the aforementioned assays, generally with an IC50 of less than about 1 xcexcM. Such a result is indicative of the intrinsic activity of the compounds in use as modulators of chemokine receptor activity.
Mammalian chemokine receptors provide a target for interfering with or promoting eosinophil and/or lymphocyte function in a mammal, such as a human. Compounds which inhibit or promote chemokine receptor function, are particularly useful for modulating eosinophil and/or lymphocyte function for therapeutic purposes. Accordingly, the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
For example, an instant compound which inhibits one or more functions of a mammalian chemokine receptor (e.g., a human chemokine receptor) may be administered to inhibit (i.e., reduce or prevent) inflammation. As a result, one or more inflammatory processes, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited. For example, eosinophilic infiltration to inflammatory sites (e.g., in asthma) can be inhibited according to the present method.
Similarly, an instant compound which promotes one or more functions of a mammalian chemokine receptor (e.g., a human chemokine) is administered to stimulate (induce or enhance) an inflammatory response, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes. For example, eosinophils can be recruited to combat parasitic infections.
In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
Diseases and conditions associated with inflammation and infection can be treated using the method of the present invention. In a preferred embodiment, the disease or condition is one in which the actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
Diseases or conditions of humans or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, particularly bronchial asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler""s syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren""s syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet""s disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn""s disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or organs. Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis.
Diseases or conditions of humans or other species which can be treated with promoters of chemokine receptor function, include, but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due congenital deficiency in receptor function or other causes; and infectious diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms); (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis); trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceral worms, visceral larva migrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larva migrans (Ancylostona braziliense, Ancylostoma caninum).
The compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic conditions, atopic conditions, as well as autoimmune pathologies.
In another aspect, the instant invention may be used to evaluate putative specific agonists or antagonists of chemokine receptors, including CCR-5 and/or CCR-3. Accordingly, the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds which modulate the activity of chemokine receptors. For example, the compounds of this invention are useful for isolating receptor mutants, which are excellent screening tools for more potent compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition. The compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors, including CCR-5 and/or CCR-3. As appreciated in the art, thorough evaluation of specific agonists and antagonists of the above chemokine receptors has been hampered by the lack of availability of non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. Thus the compounds of this invention are commercial products to be sold for these purposes.
The present invention is further directed to a method for the manufacture of a medicament for modulating chemokine receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
The present invention is further directed to the use of these compounds in the prevention or treatment of infection by a retrovirus, in particular, the human immunodeficiency virus (HIV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
In a preferred aspect of the present invention, a subject compound may be used in a method of inhibiting the binding of a chemokine to a chemokine receptor, such as CCR-5 or CCR-3, of a target cell, which comprises contacting the target cell with an amount of the compound which is effective at inhibiting the binding of the chemokine to the chemokine receptor.
The subject treated in the methods above is a mammal, preferably a human being, male or female, in whom modulation of chemokine receptor activity is desired. xe2x80x9cModulationxe2x80x9d as used herein is intended to encompass antagonism, agonism, partial antagonism, inverse agonism and/or partial agonism. In a preferred aspect of the present invention, modulation refers to antagonism of chemokine receptor activity. The term xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
The term xe2x80x9ccompositionxe2x80x9d as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms xe2x80x9cadministration ofxe2x80x9d and or xe2x80x9cadministering axe2x80x9d compound should be understood to mean providing a compound of the invention to the individual in need of treatment.
Combined therapy to modulate chemokine receptor activity and thereby prevent and treat inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities.
For example, in the treatment or prevention of inflammation, the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that may be combined with a compound of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists such as those described in U.S. Pat. No. 5,510,332, WO95/15973, WO96/01644, WO96/06108, WO96/20216, WO96/22966, WO96/31206, WO96/40781, WO97/03094, WO97/02289, WO 98/42656, WO98/53814, WO98/53817, WO98/53818, WO98/54207, and WO98/58902; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (H1-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as xcex22-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors of phosphodiesterase type IV (PDE-IV); (i) other antagonists of the chemokine receptors, especially CXCR4, CCR-1, CCR-2, CCR-3 and CCR-5; (j) cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (k) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), xcex1-glucosidase inhibitors (acarbose) and glitazones (troglitazone and pioglitazone); (l) preparations of interferon beta (interferon beta-1xcex1, interferon beta-1xcex2); (m) other compounds such as 5-aminosalicylic acid and prodrugs thereof, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
The present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art.
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating treatments with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl. Preferred agents for combination therapy include: Zidovudine, Lamivudine, Stavudine, Efavirenz, Ritonavir, Nelfinavir, Abacavir, Indinavir, 141-W94 (4-amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide), N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(S)-Nxe2x80x2(t-butylcarbox-amido)-piperazinyl))-pentaneamide, and Delavirdine. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-Nxe2x80x2-(t-butylcarbo-xamido)-piperazinyl))-pentane-amide ethanolate, and is synthesized according to U.S. Pat. No. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred inhibitors of HIV protease include nelfinavir and ritonavir. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include (xe2x88x92) 6-chloro-4(S)-cyclopropylethynyl4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, which may be prepared by methods disclosed in EP 0,582,455. The preparation of ddC, ddI and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations with the compounds of the present invention include the following: (1) Zidovudine and Lamivudine; (2) Stavudine and Lamivudine; (3) Efavirenz; (4) Ritoavir; (5) Nelfinavir; (6) Abacavir; (7) Indinavir; (8) 141-W94; and (9) Delavirdine. Preferred combinations with the compounds of the present invention further include the following (1) indinavir, with efavirenz or (xe2x88x92) 6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI and/or ddC.
Compound A in the foregoing Table is N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(S)-Nxe2x80x2-(t-butylcarboxamido)-piperazinyl))pentaneamide, preferably administered as the sulfate salt. Compound A can be prepared as described in U.S. Pat. No. 5,646,148.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.)
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
In the treatment or prevention of conditions which require chemokine receptor modulation an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made from known procedures or as illustrated. 
The preparation of cinnamate esters such as 1-3 as intermediates that can be used for the synthesis of compounds within the scope of the instant invention is detailed in Scheme 1. Cinnamate esters of structure 1-3 can be obtained commercially or can be synthesized by reacting a suitable aromatic aldehyde 1-1 with a phosphonoacetate such as 1-2 in the presence of sodium hydride or other bases such as sodium, lithium or potassium hexamethyldisilazide, potassium t-butoxide, and the like. The aldehyde 1-1 can be obtained commercially or can be prepared in a variety of ways from commercial materials (see March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 1270-1271 (1992)). 
A preparation of cyclopentane intermediates having a C-4 aryl substituent within the scope of the instant invention is detailed in Scheme 2 and can be used to prepare non-racemic cyclopentane derivatives when the resolution steps are done. Treatment of a trans-cinnamic ester such as 2-1 (see Scheme 1) with 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (2-2) in the presence of a catalytic amount of tetrakis(triphenylphosphine) palladium (0) and 1,2-bis(diphenylphosphino)ethane in THF at reflux afforded the exo-methylene cyclopentane 2-3. Hydrolysis of the ester can be done several ways, such as with aqueous sodium or lithium hydroxide in methanol or THF, to obtain the racemic acid 2-4. Resolution of the enantiomers can be accomplished by fractional crystallization from isopropanol, or other suitable solvents, of the salts with either (R)-(+)- or (S)-(xe2x88x92)-xcex1-methylbenzyl amine to give the salts 2-5 and 2-6. The non-racemic acids 2-7 and 2-8 are recovered by acidification and extraction. Reesterification to non-racemic 2-9 and 2-10 can be done in a variety of ways, such as with trimethylsilyldiazomethane or acid catalyzed esterification in methanol. 
An alternative preparation of non-racemic cyclopentane intermediates having a C-4 aryl substituent within the scope of the instant invention is detailed in Scheme 2A. Conversion of the cyclopentane acid 2-4 to the acid chloride 2-11 under standard conditions, such as with oxalyl chloride in methylene chloride with a catalytic amount of DMF, or to the mixed anhydride 2-12, prepared in situ with trimethylacetyl chloride in ether with TEA as base, followed by reaction with the preformed lithium salt of (S)-(xe2x88x92)-4-benzyl-2-oxazolidinone 2-13, afforded the two non-racemic diastereomeric products 2-14 and 2-15, which are then separable by chromatography. Hydrolysis of each diastereomer under standard conditions, such as with lithium hydroxide and hydrogen peroxide or trimethylamine-N-oxide, affords the two non-racemic acids 2-7 and 2-8. Alternatively, in order to obtain an enhanced amount of the desired diastereomer 2-14 before separation, similar conversion of the starting trans -cinnamic acid 2-16 (Scheme 1) to the chiral trans-cinnamate 2-17 followed by the ring formation reaction with 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (2-2) as detailed in Scheme 2 affords a 60:40 product mixture of 2-14:2-15. 
Preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 3. Reduction of ester 3-1 (either racemic or non-racemic) (Scheme 2), for example, with lithium borohydride, diisobutylaluminum hydride, lithium aluminium hydride, or sodium bis(2-methoxyethoxy)aluminum hydride in a suitable solvent, such as ether or THF, provides the primary alcohol 3-3. Alternatively, reduction of the acid 3-2 (either racemic or non-racemic) (Scheme 2 or 2A), for example with lithium aluminium hydride in THF, will also afford the alcohol 3-3. In cases where the Ar moiety is not amenable to salt resolution as detailed in Scheme 2, an alternative resolution can often be achieved using chiral HPLC methods to separate the enantiomers of 3-3. Oxidation of 3-3 to the aldehyde 3-4 can be carried out under numerous conditions, such as with DMSO and oxalyl chloride at low temperature, followed by triethylamine (Swern oxidation), with the Dess-Martin periodinane, with N-methylmorpholine in the presence of a catalytic amount of TPAP, or with various chromium trioxide-based reagents (see March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 1167-1171 (1992)). Reductive alkylation of a cyclic amine, such as piperidine 3-5 (see Schemes 12 to 29), using for example sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride, 1,2-dichloroethane, THF, acetonitrile or methanol, with 3-4 then provides a 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 3-6. In the cases where the R group of the piperidine is stable to ozone, ozonolysis of the exo-methylene followed by a reductive work-up with dimethyl sulfide affords the ketone 3-7. Alternatively, 3-7 can be obtained from 3-6 through a stepwise oxidation using catalytic osmium tetroxide in the presence of N-methylmorpholine-N-oxide followed by sodium periodate cleavage of the intermediate diol. A second reductive alkylation of a D- and/or L-amino-acid ester, such as the methyl, ethyl, t-butyl, benzyl or 4-methoxybenzyl ester of glycine (Rxe2x80x3=H), alanine (Rxe2x80x3=Me), valine (Rxe2x80x3=iso-Pr), leucine (Rxe2x80x3=iso-Bu), isoleucine (Rxe2x80x2=sec-Bu), cyclopropylalanine (Rxe2x80x3=CH2cycPr), cyclobutylalanine (Rxe2x80x3=CH2cycBu), cyclohexylglycine (Rxe2x80x3=cycHex) or a N-alkyl amino-acid, such as N-methyl glycine (Rxe2x80x2=Me), or a cyclic amino-acid, such as proline (Rxe2x80x2Rxe2x80x3=xe2x80x94(CH2)3xe2x80x94), with 3-7 as described above with sodium triacetoxyborohydride or sodium cyanoborohydride affords 3-8. Final deprotection of the ester under conditions to which the R group is stable, such as HCl in ether, TFA or formic acid for t-butyl and 4-methoxybenzyl esters, hydrogenation for benzyl esters or standard hydrolysis for alkyl or benzyl esters, affords the final product(s) 3-9 which are within the scope of the instant invention and which can be chemokine receptor modulators. The two individual C-1 isomers (four diastereomers when either the cyclopentyl scaffold or the amino-acid are racemic) can be separated by flash chromatography, Prep TLC or HPLC methods as either the penultimate esters 3-8 and/or the final compounds 3-9. 
An alternative route for the preparation of some 1,3,4-tri substituted cyclopentanes within the scope of the instant invention is given in Scheme 4. In the cases where the R group of the piperidine in Scheme 3 is not stable to ozone or the osmium tetroxide/sodium periodate sequence, oxidation of the exo-methylene can be done prior to the reductive alkylation of the piperidine. Thus, ozonolysis of the alcohol 4-1 (Scheme 3) followed by a reductive work-up with dimethyl sulfide affords the ketone-alcohol 4-2. Oxidation to the ketone-aldehyde 4-3 can be done as described for Scheme 3 with N-methylmorpholine/TPAP or under Swern conditions. Selective reductive alkylation of the 4-substituted piperidine 4-4 (see Schemes 12 to 29) with the aldehyde of 4-3, using for example sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride, 1,2-dichloroethane, THF, acetonitrile or methanol, then provides the 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 4-5 (same as 3-7). This can then be converted to the final product(s) 4-6 as described in Scheme 3. 
An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 5. Reductive alkylation with ketone alcohol 5-1 (Scheme 4) of a variety of amino-acid esters (See Scheme 3) affords the alcohols 5-2 and 5-3, of which 5-2 is the major product (lower Rf when Rxe2x80x3 is (S), higher Rf when Rxe2x80x3 is (R)) and 5-3 is the minor product (higher Rf when Rxe2x80x3 is (S), lower Rf when Rxe2x80x3 is (R)). Separation of the individual diastereomers (2 when both reactants are non-racemic, 4 when only one is non-racemic) can be done at this intermediate or at a later step. Oxidation of 5-2 and/or 5-3 to the aldehyde(s) 5-4 can be done as described in Scheme 3, preferably now with N-methylmorpholine/TPAP due to the presence of the secondary Nxe2x80x94H. Reductive alkylation of a 4-substitutedpiperidine 5-5 (see Schemes 12 to 29) with the aldehyde of 5-4, using for example sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride, 1,2-dichloroethane, THF, acetonitrile or methanol, then provides the 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 5-6. The intermediate ester(s) 5-6 can then be converted to the final product(s) 5-7 as described in Scheme 3. 
An alternative preparation of the intermediates 5-2 and 5-3 in Scheme which reverses the C-1 isomeric selectivity is shown in Scheme 5A. Silylation of the alcohol moiety of 5-1 (Scheme 4) gives the silyl ether 5-10. Alternatively, silylation of the alcohol 5-8 (Scheme 3) gives 5-9 which on ozonolysis can also afford the silyl ether 5-10. Reductive alkylation of the aforementioned amino-acid esters now using the silyl ether 5-10 affords the products 5-11 and 5-12 in an essentially opposite ratio as is obtained in Scheme 5 for 5-2 and 5-3. TBAF desilylation then affords primarily 5-3. Thus, the preferred C-1 orientation can be selected for depending on the requirements of the desired final compounds. 
An alternative preparation of the intermediates 5-2 or 5-3 in Scheme 5 and intermediates 5-11 and 5-12 in Scheme 5A when Rxe2x80x2 is Me is shown in Scheme 5B. When 5-13 is formed in the reductive amination with ketones 5-1 (Rb=H) or 5-10 (Rb=TBDMS), a second reductive amination of 5-13 with formaldehyde, either in the presence of hydrogen and a suitable catalyst, such as 10% Pd/C or Pearlman""s catalyst, in methanol or standard reaction with sodium triacetoxyborohydride in 1,2-dichloroehthane, affords the methylated intermediates 5-14. These intermediates can be further elaborated to the final products as described in Scheme 5 and/or 5A. 
An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 6. Reductive alkylation of benzylamine with ketone-alcohol 6-1 (Scheme 4, either racemic or non-racemic), using for example sodium triacetoxyborohydride or sodium cyanoborohydride, gives 6-2 which can be hydrogenated under standard conditions in methanol in the presence of a palladium catalyst, for example Pd/C or Pearlman""s catalyst and using either hydrogen under pressure or ammonium formate at reflux, to afford the primary amine 6-3. Reaction of the amine with CBZ chloride or Boc anhydride gives the amine protected carbamates 6-4 and 6-5 as a mixture of C-1 isomers which can be separated. Oxidation to the aldehydes 6-6 and 6-7 is carried out under Swern conditions or with N-methylmorpholine/TPAP. The relative stereochemistry of the C-1 to the C-3 and C-4 substituents was determined by NMR Noe experiments on either the alcohols 6-4 and 6-5 or the aldehydes 6-6 and 6-7. Reductive alkylation of a 4-substitutedpiperidine 6-8 with the individual aldehydes 6-6 and 6-7, using for example sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride, 1,2-dichloroethane, THF, acetonitrile or methanol, then provides each of the C-1 amino-protected isomeric 3-((4-substituted piperidin-1-yl)methyl)cyclopentane derivatives 6-9 and 6-10. Deprotection of the C-1 amino with either TFA (for Ra=t-butyl) or standard hydrogenation (for Ra=Bn) depending on the stability of the piperidine R group affords the amines 6-11 and 6-12. These amines can then be individually reductively alkylated as above with 2-oxo-acetic acids, such as 2-oxovaleric (Rxe2x80x3=n-Pr), 4-methyl-2-oxovaleric (Rxe2x80x3=iso-Bu), 2-oxophenylacetic (Rxe2x80x3=Ph), to afford the final compounds 6-13 and 6-14 and 6-15 and 6-16 as mixtures of the Rxe2x80x3 isomers. In the case of Rxe2x80x3=iso-Bu and non-racemic cyclopentyl scaffold, comparison of the HPLC of these products with those obtained in Scheme 5 allowed the stereochemical assignments of all the final products and intermediates. 
An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 7. Reductive alkylation, using for example sodium triacetoxyborohydride or sodium cyanoborohydride, of an alkyl amine with the ketone 7-1 (Schemes 3 or 4) gives 7-2 as a mixture of C-1 isomers which may be separated. Alternatively, carbamate 7-3 (see Scheme 6) can be alkylated with an alkyl or allyl halide, such as 1-bromo-2-methylprop-2-ene, and a strong base, such as sodium hydride in DMF, followed by hydrogenation under standard conditions to reduce the allyl. When Ra is Bn, removal the CBZ can occur simultaneously to give the same amine intermediate 7-2. When Ra is t-butyl, a subsequent reaction with TFA is required to give 7-2. Alkylation of the amine with t-butyl or benzyl bromoacetate affords 7-5 which can be converted to the desired final compound(s) 7-6 as described in Scheme 3.
An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 8. Reductive alkylation, using for example sodium triacetoxyborohydride or sodium cyanoborohydride, of glycine t-butyl, benzyl or PMB ester with the ketone-alcohol 8-1 (Scheme 4) gives 8-2 as a mixture of C-1 isomers. A second reductive alkylation with a ketone or aldehyde affords the N-alkyl glycine derivatives 8-3 and 8-4 which can be separated chromatographically either before and/or after the second alkylation. Also, the order of the steps can be reversed such that reductive alkylation of an amine with 8-1 first to give 8-5, followed by alkylation with an alkyl or benzyl bromoacetate as in Scheme 7, affords 8-3 and 8-4. These reactions generally give 8-3 as the predominate product. Individual oxidation of the alcohols 8-3 and 8-4 can be done either under Swern conditions or using the N-methylmorpholine/TPAP method to give the aldehyde intermediate(s) followed by a second or third reductive alkylation of a 4-substitutedpiperidine 8-6, using for example sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride, 1,2-dichloroethane, THF, acetonitrile or methanol, which then provides the 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 8-7. This intermediate can then be converted to the final product(s) 8-8 as described in Scheme 3.
An alternative preparation of the intermediates 8-3 and 84 in Scheme 8 which again reverses the C-1 isomeric selectivity is shown in Scheme 8A. Silylation of the alcohol moiety of 8-1 (Scheme 4) gives the silyl ether 8-9. Alternatively, silylation of the alcohol 8-10 (Scheme 3) gives 8-11, which on ozonolysis can also afford the silyl ether 8-9. Reductive alkylation now using the silyl ether 8-9 gives 8-12 and 8-13 followed by the second reductive alkylation with an aldehyde or ketone affords the products 8-14 and 8-15 in an essentially opposite ratio as is obtained in Scheme 8 for 8-3 and 8-4. TBAF desilylation then affords primarily 8-4. Separation of the C-1 isomers can usually be achieved at one or more of the intermediate steps. Thus, the preferred C-1 orientation can be selected for depending on the requirements of the desired final compounds. 
Several other alternative routes for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention are given in Scheme 9. Reductive alkylation, using for example sodium triacetoxyborohydride or sodium cyanoborohydride, of an amino-acid ester having dialkyl substitution with the ketone-alcohol 9-1 (Scheme 4) gives 9-2 as a mixture of C-1 isomers which may be separated and carried on to the final product(s) 9-3 individually or as a mixture as detailed in Scheme 5. Alternatively, a second reductive alkylation of 9-2 as in Scheme 8 affords 9-4 which may be separable or used as a mixture to give final product(s) 9-5. Also, more extended amino-acid esters, such as xcex2-alanine ester (9-6, n=1) or 4-aminobutyrate (9-6, n=2), which may also be substituted on the chain or on N, can be employed to give 9-7. These intermediates can then be converted to final product(s) 9-8 as described in Scheme 5 and/or 8. 
An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 10. Reductive alkylation, using for example sodium triacetoxyborohydride or sodium cyanoborohydride, of a cyclic secondary amino-acid 10-1, such as D- or L-proline t-butyl ester (n=0), xcex2-proline t-butyl ester (n=0), 2-, 3-, and 4-t-butylcarboxypiperidine (n=1), with the ketone-alcohol 10-2 (Scheme 4) gives 10-3 and 10-4 as a mixture of C-1 isomers which may be separated. These intermediates can then be converted to the final product(s) as described in Scheme 5.
An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 11. Reductive alkylation, using for example sodium triacetoxyborohydride or sodium cyanoborohydride, of a cycloalkyl amino-acid 11-1, such as 1-aminocyclopentane carboxylic acid t-butyl ester (Z=single bond) or a heterocyclic amino-acid, such as 4-aminomorpholin-2-yl carboxylic acid t-butyl ester (Z=O) with the ketone-alcohol 11-2 (Scheme 4) gives 11-3 and 11-4 as a mixture of C-1 isomers which may be separated. These intermediates can then be converted to the final product(s) as described in Scheme 5.
One method of generating 4-aryl piperidines as intermediates is given in Scheme 12. Reaction of commercially available 12-1 or 12-2 with a strong base, such as LDA, LHDMS, NaHMDS, KHMDS, or NaH followed by treating with a suitable triflating agent, such as 5-chloropyrid-2-yl triflimide (12-3), N-phenyl triflimide or triflic anhydride, provides enol triflates 12-4 or 12-5. Heating with commercially available aryl boronic acids in the presence of a suitable palladium(0) catalyst such as tetrakis triphenylphosphine palladium, a base (such as potassium carbonate or sodium carbonate), in a solvent such as DME, THF, dioxane or toluene/ethanol, effects coupling to provide the unsaturated products 12-6 or 12-7. In the case of 12-7, treatment with a heterogeneous palladium catalyst in methanol or ethanol in an atmosphere of hydrogen provides the desired intermediate 12-8. Alternatively, the Boc protected derivative 12-6 is hydrogenated under standard conditions to provided the saturated piperidine 12-9, which is then deprotected under acidic conditions (such as trifluoroacetic acid and anisole in methylene chloride or HCl in methanol), to provide 12-8 as a salt, which is then utilized as the cyclic secondary amine component as shown above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11.
An alternative method of generating 4-aryl piperidines as intermediates is given in Scheme 13. Reaction of commercially available 13-1 with an aryl magnesium halide or with an aryllithium (in the presence or absence of anhydrous cerium trichloride) provides tertiary alcohol 13-2, which upon treatment under acidic conditions (such as sulfuric acid, HBr in acetic acid, HCl in acetic acid) or under dehydrating conditions (such as with thionyl chloride in pyridine or with phosphorus oxychloride) provides olefin 13-3. Hydrogenation under standard conditions using either hydrogen gas or a hydrogen donor (such as ammonium formate or cyclohexene) effects reduction of the double bond and cleavage of the N-benzyl group to provide the desired intermediate 13-4. Under some circumstances it may be preferable to reduce the double bond under non -hydrogenolytic conditions, for example with triethylsilane and trifluoroacetic acid or under dissolving metal conditions (for example, sodium or lithium metal in ammonia or a lower alkyl amine). If the N-benzyl group is not removed under these conditions, it may be cleaved by treatment with either vinyl chloroformate and then hydrogen chloride or by treatment with 2-chloroethyl chloroformate followed by heating in methanol. The product 13-4 is then utilized as the cyclic secondary amine component as shown above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
One route for the preparation of 4-hydroxy-4-(3-arylpropyl)piperidines is given in Scheme 14. Treatment of commercially available 4-piperidones 14-1 or 14-2 with trimethylsulfonium iodide and sodium hydride in dimethyl sulfoxide at or above room temperature provides Spiro epoxides 14-3 or 14-4. Addition of the lithium salt of trimethylsilylacetylene to these epoxides in the presence of lithium perchlorate in THF at 0 degrees C., followed by treatment of the crude intermediate with potassium carbonate in methanol, affords the acetylenic alcohols 14-5 or 14-6. Heating of these alkynes with an aromatic halide or triflate in the presence of copper(I) iodide, a palladium catalyst such as bis(triphenylphosphine)palladium dichloride or bis(triphenylphosphine)palladium diacetate in the presence of a tertiary amine base such as triethylamine or tributylamine, then provides coupling products 14-7 or 14-8. In the case of the N-benzyl protected intermediate 14-8, hydrogenation/hydrogenolysis under standard conditions (for example 10% Pd/C in an atmosphere of hydrogen) provides desired intermediate 14-9. For the Boc protected species 14-7, hydrogenation as above provides the saturated piperidine 14-10, and treatment of this compound under anhydrous acidic conditions (for example, trifluoroacetic acid and anisole in methylene chloride, or acetyl chloride in methanol) then yields the salt of intermediate 14-9. This compound is then utilized as the cyclic secondary amine component as shown above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. Alternatively, if 4-piperidone is attached directly to the functionalized alkylcyclopentane framework described above and no functionality in the alkylcyclopentane would be affected, then the chemistry described herein can be carried out treating the aforementioned alkylcyclopentane segment as xe2x80x98Pxe2x80x99 given in Scheme 14. 
An alternative route for the preparation of 4-hydroxy-4-(3-arylpropyl)piperidines is given in Scheme 15. Treatment of commercially available 4-piperidones 15-1 or 15-2 with a suitable allyl metal compound (such as allylmagnesium bromide or allyltributylstannane (in the presence of boron trifluoride etherate) in THF, ether or dichloromethane, provides adducts 15-3 or 15-4. Hydroboration with a dialkylborane, such as 9-borabicyclo[3.3.1]nonane (9-BBN), followed by treatment with an aryl halide (the halides preferably being bromide or iodide) or aryl triflate and sodium methoxide in the presence of a suitable soluble palladium catalyst, for example Pd(dppf)Cl2, in warm to refluxing THF, provides the 3-arylpropyl derivatives 15-5 and 15-6. For benzylamine 15-6, hydrogenolysis under standard conditions provides the desired intermediate 15-7. For Boc substituted piperidine 15-5, exposure to suitable anhydrous acidic conditions (for example trifluoroacetic acid and anisole in methylene chloride or HC in methanol at temperatures from 0-25 degrees C.) affords the salt of 15-7. This compound is then utilized as the cyclic secondary amine component as shown above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. Alternatively, if no functionality are present in the alkylcyclopentane framework that would be adversely effected by the above mentioned chemistry, then 4-piperidone may be attached directly to the alkylcyclopentane framework described above, and the chemistry described in this paragraph can be carried out equating the alkylcyclopentane segment to the group xe2x80x98Pxe2x80x99 given in Scheme 15, structures 1 through 6. 
A route for the preparation of 4-(3-arylpropyl)piperidines is given in Scheme 16. Treatment of phosphonoacetate 16-1 with KHMDS followed by addition of commercially available N-Boc 4-piperidone 16-2 provides unsaturated ester 16-3. Hydrogenation of 16-3 followed by hydrolysis to the acid and then reduction with borane.ethyl sulfide then affords primary alcohol 16-4. Mild oxidation of 16-4 under Swern conditions provides the corresponding aldehyde, which upon treatment with the Wittig reagent prepared from methyltriphenylphosphonium iodide and KHMDS yields olefin 16-5. Hydroboration with a dialkylborane, such as 9-borabicyclo[3.3.1]nonane (9-BBN), followed by treatment with an aryl halide (the halides preferably being bromide or iodide) or aryl triflate in the presence of a suitable soluble palladium catalyst, for example PdCl2DPPF, in warm to refluxing THF, provides the 3-arylpropyl derivative 16-6. Removal of the Boc group under acidic conditions, for example with HCl in methanol or with trifluoroacetic acid in methylene chloride, then affords the 1-unsubstituted piperidine 16-7, which can then be employed as the secondary amine component in the syntheses described above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
Another route for the preparation of 4-(3-arylpropyl)piperidines is given in Scheme 17. Treatment of phosphonoacetate 17-1 with KHMDS followed by addition of commercially available N-Boc-4-piperidone 17-2 provides unsaturated ester 17-3. Hydrogenation of 17-3 followed by hydrolysis to the acid and then reduction with borane.methyl sulfide then affords primary alcohol 17-4. Formation of the alkyl iodide with triphenylphosphine and iodine in the presence of imidazole followed by treatment with triphenylphosphine provides phosphonium salt 17-5. Deprotonation with a suitable base, for example, KHMDS, LiHMDS, NaHMDS, NaH, LDA, or KH affords the Wittig agent in situ, which upon treatment with a suitable aromatic aldehyde yields the unsaturated derivative 17-6. Hydrogenation under standard conditions provides 17-7, and removal of the Boc group with HCl in methanol or with other acidic conditions then provides the 1-unsubstituted piperidine 17-8, which can then be employed as the secondary amine component in the syntheses described above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
Preparation of piperidines with a 4-(3-aryl-3,3,-difluoropropyl) side chain is given in Scheme 18. Treatment of commercially available 18-1 with Boc anhydride provides protected piperidine 18-2. Oxidation, for example with the Dess-Martin reagent, by a Swern oxidation, or other known methods provides aldehyde 18-3. Condensation under Homer-Wadsworth-Emmons conditions affords unsaturated ester 18-4, which is hydrogenated to ester 18-5 and then hydrolysed to acid 18-6. Formation of the N-methyl-N-methoxy amide 18-7 is carried out employing standard activating agents such as EDC. Weinreb amide 18-7 is then allowed to react with an arylmetal reagent, such as an aryl magnesium halide or an aryllithium, to provide ketone 18-8. Cleavage of the protecting Boc group under acidic conditions yields 18-9, which is reprotected with a carbobenzyloxy group under standard conditions, to afford 18-10. Formation of dithiolane 18-11 with ethanedithiol and boron trifluoride is followed by treatment with 1,3-dibromo-3,3-dimethylhydantoin and pyridine-hydrogen fluoride complex at or around xe2x88x9278 degrees C., to provide gem-difluoro derivative 18-12. Removal of the CBZ group under reductive conditions provides piperidine 18-13, which may be employed directly as the secondary amine in chemistry described above. Alternatively, if additional purification is desired, 18-13 may be protected with a Boc group to afford 18-14. After suitable purification, the Boc group is removed under acidic conditions at or near 0 degrees C. A controlled, basic work-up then provides 18-13, suitable for use as described above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
A route for the preparation of 4-(3-arylpropyl)piperidines is given in Scheme 19. Treatment of phosphonoacetate 19-1 with KHMDS followed by addition of commercially available N-Boc-4-piperidone 19-2 provides unsaturated ester 19-3. Hydrogenation of 19-3 followed by hydrolysis to the acid and then reduction with borane-methyl sulfide then affords primary alcohol 19-4. Mild oxidation of 19-4 under Swern conditions provides the corresponding aldehyde, which upon treatment with the Wittig reagent prepared from methyltriphenylphosphonium iodide and KHMDS yields olefin 19-5. Palladium-catalyzed arylation of 19-5 then affords unsaturated derivative 19-6. Addition of dibromocarbene (generated in situ from bromoform and potassium hydroxide) provides cyclopropyl derivative 19-7. Debromination is carried out by slow addition of tributyltin hydride in the presence of the radical initiator AIBN. Removal of the nitrogen protecting group under acidic conditions, for example, hydrochloric acid in methanol, affords cyclopropyl piperidine 19-8, which can then be employed as the secondary amine component in the syntheses described above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
A route for the preparation of 4-(3-aryl-2-methylpropyl)piperidines is given in Scheme 20. Treatment of commercially available 3-chloropropionic acid (20-1) with triphenylphosphine in refluxing toluene provides phosphonium salt 20-2. Treatment with sodium hydride in DMSO/THF provides the ylide in situ, which upon addition of piperidone 20-3 affords the adduct 20-4. Reduction of the double bond, for example with hydrogen gas in the presence of a palladium catalyst, gives acid 20-5. Treatment of 20-5 with trimethylacetyl chloride and triethylamine generates the mixed anhydride in situ, which upon treatment with the lithium salt of 4-(S)-benzyl-2-oxazolidone yields 20-6. Deprotonation of 20-6 with sodium hexamethyldisilazide, followed by addition of methyl iodide, provides alpha-methyl derivative 20-7. Reduction of acyl-oxazolidone 20-7 with lithium borohydride produces the corresponding primary alcohol, which is converted to primary iodide 20-8 with iodine, triphenylphosphine and imidazole in toluene. Coupling with phenyl magnesium bromide in the presence of Ni(fdpp)Cl2 affords aralkyl derivative 20-9, which is then deprotected under acidic conditions to provide piperidine 20-10. Piperidine 20-10 can then be employed as the secondary amine component in the syntheses described above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
A route for the preparation of 4-(3-aryl-1-methylpropyl)piperidines is given in Scheme 21. Addition of the anion of phosphonoester 21-1 to piperidone 21-2 provides unsaturated ester 21-3. Reduction of the double bond and hydrolysis of the ester affords acid 21-4. Treatment of 21-4 with triethylamine and trimethylacetyl chloride provides the mixed anhydride in situ, which is then coupled with the lithium salt of 4-(S)-benzyl-2-oxazolidone, to yield acyl oxazolidone 21-5. Deprotonation with sodium hexamethyldisilazide followed by addition of methyl iodide provides 21-6. Reduction of 21-6 with lithium borohydride affords alcohol 21-7, which upon treatment with iodine, triphenylphosphine and imidazole in toluene is converted to iodide 21-8. Treatment with triphenylphosphine gives phosphonium salt 21-9, which is converted to the ylide with potassium hexamethyldisilazide. Addition of an aryl aldehyde generates unsaturated aryl derivative 21-10. Hydrogenation provides saturated piperidine 21-11, which is then deprotected under acidic conditions to afford 21-12, which can then be employed as the secondary amine component in the syntheses described above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
A route for the preparation of 4-(3-aryl-3-methylpropyl)piperidines is given in Scheme 22. Treatment of commercially available 4-(R)-phenylbutyric acid (22-1) with ethyl chloroformate and triethylamine forms the asymmetric anhydride in situ, which upon treatment with sodium borohydride provides primary alcohol 22-1. Alternatively, this conversion can be carried out by treatment of 22-1 with borane-THF. Activation of the hydroxy group of 22-2 with methanesulfonyl chloride in the presence of a hindered base such as N,N-(diisopropyl)ethylamine, followed by displacement with sodium iodide in refluxing acetone affords iodide 22-3. Heating with triphenylphosphine in toluene provides the phosphonium salt 22-4. Deprotonation of this salt with a strong base, for example n-butyl lithium generates the Wittig reagent in situ, which is then allowed to react with N-Boc-4-piperidone, to yield olefin 22-5. Hydrogenation of the double bond followed by treatment with acid, for example HCl in methanol, then provides the secondary amine salt 22-6, which can then be employed as the secondary amine component in the syntheses described above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
A route for the preparation of 4-(3-(benzimidazol-2-yl)propyl)piperidines is given in Scheme 23. Protection of piperidine 23-1 under reductive amination conditions provides benzylamine 23-2. Oxidation to aldehyde 23-3 is carried out under standard conditions, for example with the Dess-Martin periodinane. Addition of ester 23-4 provides unsaturated olefin 23-5, which upon reduction affords ester 23-6. Reduction with lithium aluminum hydride or other strong hydride reducing agents followed by mild oxidation provides aldehyde 23-7. Upon combination with diamine 23-8 under reductive alkylation conditions affords the N-alkylated derivative 23-9. Treatment with orthoformate derivative 23-10 in the presence of acid yields benzimidazole 23-11, which upon hydrogenation with palladium on carbon under transfer hydrogenation conditions generates piperidine 23-12, which can then be employed as the secondary amine component in the syntheses described above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
Procedures for synthesizing certain CCR5 receptor modulators containing 4-(heteroarylamino)piperidine functionality are shown in Scheme 24. After protecting commercially available 4-bromopiperidine, the bromide is displaced with sodium azide, and the azide is reduced, for example by catalytic reduction, to provide aminopiperidine 24-3. Treatment of 24-3 with an aryl or heteroaryl halide (the halide preferably being bromide) in the presence of a palladium catalyst, sodium t-butoxide and a suitable bidentate ligand (such as BINAP), according to the conditions of Buchwald et al, provides arylamine 24-4. Direct acidic deprotection of 24-4 may be carried out to provide secondary amine 24-5. Alternatively, amine 24-4 may be alkylated with a suitable alkyl, alkenyl or alkynyl halide (wherein the halide is bromo or iodo in the case of an alkyl group and chloro or bromo in the case of allylic or propargylic functionality) in the presence of a strong base, such as potassium hexamethyldisilazide, to provide trisubstituted amine 24-6. Acidic deprotection, for example, trifluoroacetic acid and anisole in dichloromethane, or methanolic hydrochloric acid, then provides the bis ammonium salt, which in the case of trifluoroacetic acid deprotection, is compound 24-7. The secondary piperidines 24-5 and 24-7 are then utilized as the cyclic secondary amine component as shown above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
For certain aminoheterocycles, direct displacement of a halogen may provide improved access to the desired intermediates. For example, as shown in Scheme 25, unsubstituted and substituted 2-chloropyrimidines 25-2 may be coupled directly to amine 25-1 in the presence of a suitable base, such as triethylamine, to provide aminopyrimidine 25-3. Acidic deprotection then affords 25-4. Alternatively, 25-3 may be alkylated in the presence of a strong base to provide 25-5, which upon deprotection gives intermediate 25-6. The secondary piperidines 25-4 and 25-6 are then utilized as the cyclic secondary amine component as shown in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
One preparation of piperidine subunits containing functionalized pyrazoles at C4 of the piperidine is given in Scheme 26. Treatment of piperidine 26-1 with carbonyldiimidazole to form the acyl imidazole, followed by addition of a dialkyl or alkyl-aryl ketone (26-2) in the presence of lithium diisopropylamide (LDA) gives the diketone 26-3. Treatment with a monoalkyhydrazine in an alcohol solvent at temperatures between 0 to 100 degrees C. (preferably about 50 degrees C.) in the presence of a hindered base such as DIPEA then provides a mixture of the isomeric pyrazoles 26-4 and 26-5. After separation of these compounds by chromatography or crystallization, the individual products are deblocked under acidic conditions (for example trifluoroacetic acid and anisole with or without methylene chloride as a co-solvent) to provide the piperidine salts 26-6 and 26-7, which are then used as the cyclic secondary amine component as shown above in Scheme 2 and in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
Another preparation of piperidine subunits containing functionalized pyrazoles at C4 of the piperidine is given in Scheme 27. Treatment of commercially available bromide 27-1 with triphenylphosphine in refluxing toluene provides phosphonium salt 27-2, which after treatment with a strong anhydrous base such as potassium hexamethyldisilazide in toluene and the piperidine ketone 27-3 provides the olefin 27-4. Hydroboration followed by an oxidative work-up with chromic acid then affords ketone 27-5. Selective formylation of 27-5 with methyl formate in the presence of potassium t-butoxide selectively affords ketoaldehyde 27-6. Heating of 27-6 with a monoalkylhydrazine in methanol in the presence of a hindered (or insoluble) base such as DIPEA then provides a mixture of the 1,4-disubstituted pyrazoles 27-7 and 27-8. After separation by chromatography, crystallization or fractional distillation, the purified isomers are deprotected under transfer hydrogenation conditions to provide the piperidines 27-9 and 27-10, which are then utilized as the cyclic secondary amine component as shown above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
A preparation of piperidine subunits containing 3,5-difunctionalized pyrazoles linked through N-1 to C-4 of the piperidine is given in Scheme 28. Treatment of commercially available hydrazine 28-1 with diketone 28-2 in ethanol at 0 to 90 degrees C. (preferably 50 degrees C.) in the presence of DIPEA provides a mixture of pyrazoles 28-3 and 28-4, which are separated under standard conditions, for example HPLC. Removal of the benzyl groups by transfer hydrogenation provides the secondary piperidines 28-5 and 28-6, which are then utilized as the cyclic secondary amine component as shown above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
A preparation of 4-(benzimidazol-1-yl)piperidine subunits is given in Scheme 29. Combining piperidone 29-1 and diamine 29-2 in the presence of sodium triacetoxyborohydride under dehydrating conditions provides reductive amination product 29-3. Addition of a suitably substituted ortho ester 29-4 in the presence of a acid catalyst, for example concentrated hydrochloric acid, provides benzimidazole intermediate 29-5. Deprotection under reductive conditions, for example with palladium on carbon under transfer hydrogenation conditions, then provides secondary amine 29-6, which is then utilized as the cyclic secondary amine component as shown above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. 
Another method of preparing compounds within the scope of the instant invention is given in Scheme 30 in which most of the chemistry is done on a resin and thus simplifies the isolations. Thus, the keto-acid 30-3, prepared either by standard hydrolysis of the ester 30-1 or oxidation of the exo-methylene of 30-2 with ozone in methanol at xe2x88x9270xc2x0 C. followed by treatment with dimethyl sulfide, is first activated as its anhydride 30-4 by treatment with a dehydrating agent, such as dicyclohexylcarbodiimide or diisopropylcarbodiimde, in a suitable solvent, such as THF or methylene chloride or a mixture of these, with a catalytic amount of DMAP. Reaction of 30-4 with a suitable sulfonamide linker 30-5 affords the resin-bound cyclopentanone 30-6. Reductive amination of various amines with 30-6 affords the resin-bound amino derivative 30-7. Acylation can be done under standard conditions, such as with chloroformates, usually in the presence of an amine base, such as triethylamine, diisopropylethylamine, N-methylmorpholine, or pyridine, to afford the resin-bound amine derivative 30-8. Activation of the resin sulfonamide linker with trimethylsilyldiazomethane and displacement with an amine, such as the piperidine 30-9 (see Schemes 12-29) in which R must be stable to borane-dimethyl sulfide reduction, gives the corresponding amide 30-10. Subsequent reduction of the amide 30-10 with borane-dimethyl sulfide and removal of the carbamate, such as with TFA for a Boc derivative or standard hydrogenation for a CBZ derivative, affords the amine 30-11, which can be converted to the desired final compound as detailed in Scheme 6.
In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of further-illustration only and are not intended to be limitations on the disclosed invention.
Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash chromatography was carried out on silica gel (230-400 mesh). NMR spectra were obtained in CDCl3 solution unless otherwise noted. Coupling constants (J) are in hertz (Hz). Abbreviations: diethyl ether (ether), triethylamine (TEA), N,N-diisopropylethylamine (DIEA) saturated aqueous (sat""d), room temperature (rt), hour(s) (h), minute(s) (min).
HPLC A. Retention time using the following conditions: Column: YMC ODS A, 5 xcexc, 4.6xc3x9750 mm; Gradient Eluant: 10:90 to 90:10 v/v CH3CN/H2O+0.5% TFA over 4.5 min, hold 30 sec; Detection: PDA, 210-400 nm; Flow Rate: 2.5 mL/min.
HPLC B. Retention time using the following conditions: Column: Analytical Sales and Services Advantage HL C18 5xcexc 4.6xc3x97100 mm column; Gradient Eluant: 10:90 to 90:10 v/v CH3CN/H2O+0.5% TFA over 10 min, hold 2 min; Detection: PDA, 200-400 nm; Flow Rate: 2.25 mL/min.
The following are representative Procedures for the preparation of the piperidines used in the following Examples or which can be substituted for the piperidines used in the following Examples which may not be commercially available.
HPLC A. Retention time using the following conditions: Column: YMC ODS A, 5 xcexc 4.6xc3x9750 mm; Gradient Eluent: 10:90 to 90:10 v/v acetonitrile/water+0.5% TFA over 4.5 min, hold 30 sec; Detection: PDA, 210-400 nm; Flow Rate: 2.5 mL/min.
HPLC B. Retention time using the following conditions: Column: Analytical Sales and Services Advantage HL C18 5 xcexc 4.6xc3x97100-mm column; Gradient Eluent: 10:90 to 90:10 v/v acetonitrile/water+0.5% TFA over 10 min, hold 2 min; Detection: PDA, 200-400 nm; Flow Rate: 2.25 mL/min.
The following are representative Procedures for the preparation of the piperidines used in the following Examples or which can be substituted for the piperidines used in the following Examples and which are not commercially available.
Step A: 1-(1-(t-Butoxycarbonyl)piperidin-4-yl)4-phenylbutane-1,3-dione
Method A:
n-Butyl lithium (100 mL, 0.16 mole) was added to a stirred solution of diisopropylamine (16.16 g, 22.4 mL, 0.16 mole, distilled) in THF (450 mL) at 0xc2x0 C. over 45 min under nitrogen. Stirring was continued for 10 min at 0xc2x0 C. after the addition was complete. After cooling to xe2x88x9278xc2x0 C., phenylacetone (21.45 g, 21.13 mL, 0.16 mole) in THE (100 mL) was added dropwise over 15 min with stirring. This solution was stirred at xe2x88x9278xc2x0 C. for 1 h. Meanwhile, a solution of N-Boc isonipecotic acid (18.32 g, 0.080 mole) and carbonyl diimidazole (12.98 g, 0.080 mole) in THF (150 mL) was prepared. After stirring for 15 min, this solution was canulated into the enolate solution dropwise over 15 min. The reaction was stirred at  less than xe2x88x9270xc2x0 C. for 1 h and then allowed to warm to rt over 3 h. The reaction was quenched with 1M citric acid (250 mL) and stirred for 16 h. The organic layer was separated and washed with 250 mL each of saturated sodium bicarbonate solution, water and brine. After drying over sodium sulfate, the organic layer was concentrated to give an oil. The residue was purified by FC on silica gel (10% ethyl acetate in 60-80xc2x0 C. petroleum ether) to give separation of the two isomers. The first higher Rf fractions afforded pure title compound as the minor product (3.5 g) as an oil.
1H NMR (500 MHz, CDCl3): xcex47.34-7.37 (m, 2 H), 7.25-7.31 (m, 3 H), 5.46 (s, 1 H), 4.11-4.17 (m, 2 H), 3.63 (s, 2 H), 2.70-2.76 (m, 2 H), 2.29 (tt, J=11.7 and 3.7 Hz, 1 H), 1.75-1.80 (m, 2 H), 1.47-1.61 (m, 2 H), 1.47 (s, 9 H). MS (ESI): m/z 346 (M+1).
The lower Rf fractions contained phenylacetone and major product 1-(1-(t-butoxycarbonyl)piperidin-4-yl)-2-phenylbutane-1,3-dione from which the latter crystallized on standing to give 7 g white solid (m.p. 105-106xc2x0 C.).
1H NMR (360 MHz, CDCl3): xcex415.23 (s, 1 H), 7.3-7.45 (m, 3H), 7.15-7.2 (m, 2 H), 4-4.1 (m, 2 H), 2.35-2.50 (m, 2 H), 2.2-2.3 (m, 1 H), 1.87 (s, 3 H), 1.5-1.75 (m, 4 ), 1.43 (s, 9 H). MS (ESI): m/z 346 (M+1).
Method B:
Step B1: 1-(t-Butoxycarbonyl)piperidine-4-N-methyl-N-methoxycarboxamide
N-Boc isonipecotic acid (13.56 g, 59.2 mmol), N,O-dimethyl hydroxylamine hydrochloride (8.65 g, 88.7 mmol), and 1-hydroxybenzotriazole hydrate (15.9 g, 118 mmol) were dissolved in DMF (225 mL) in a 500 mL round-bottom flask and diisopropylethylamine (15.3 g, 20.6 mL, 118.3 mmol) was then added with stirring at rt. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (17.01 g, 88.74 mmol) was added in several portions over 10 min with stirring. After 22 h, the reaction mixture was poured into a water and ice mixture (600 mL) and was extracted with ethyl acetate (5xc3x97125 mL). The combined organic layers were washed with 1N HCl (2xc3x97200 mL), 5% sodium bicarbonate (2xc3x97200 mL), water and brine, dried over sodium sulfate and concentrated to give the title compound (15.58 g) as a yellowish oil.
1H NMR (500 MHz, CDCl3): xcex44.11-4.20 (m, 2 H), 3.72 (br s, 3 H), 3.20 (br s, 3 H), 2.75-2.86 (m, 3 H), 1.63-1.76 (m, 4 H), 1.47 (s, 9 H).
Step B2: 4-Acetyl-1-(t-butoxycarbonyl)piperidine
After dissolving the Weinreb amide from Step B1 in anhydrous ether (400 mL) under nitrogen and cooling the solution in an ice bath, 1.4M methyl magnesium bromide (55 mL) in 3:1 toluene and THF was added with stirring and cooling over 30 min. After stirring at 0xc2x0 C. for 1 h, the reaction was poured into a mixture of ice water (400 mL) and acetic acid (8 mL, 150 mmol). The layers were separated and the aqueous layer was extracted twice with ether. The combined organic layers were washed with 0.1N HCl (200 mL), 3% sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated to give the crude product (14.322 g). FC (20-80% ethyl acetate in hexanes) gave the title compound (9.440 g) as a yellowish oil. Rf: 0.27 (25% ethyl acetate in hexanes). Some starting Weinreb amide was also recovered (3.212 g). Rf: 0.10 (25% ethyl acetate in hexanes).
1H NMR (500 MHz, CDCl3): xcex44.07-4.14 (m, 2 H), 2.75-2.83 (m, 2 H), 2.46 (tt, J=11.3 and 3.8 Hz, 1 H), 2.17 (s, 3 H), 1.82-1.87 (m, 2 H), 1.48-1.57 (m, 2 H), 1.46 (s, 9 H).
Step B3: 1-(1-(t-Butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione
To a suspension of 60% sodium hydride (1.07 g) in THF (15 mL) at 0xc2x0 C. was added a solution of 4-acetyl-1-(t-butoxycarbonyl)piperidine from Step B2 (3.03 g, 13.3 mmol) and methyl phenylacetate (6.01 g, 39.9 mmol) in THF (6 mL) over 20 min. The reaction was stirred for another 4 h as it was allowed to warm to rt. The mixture was diluted with ether (30 mL) and poured into 1N HCl. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers were washed with brine (150 mL), dried over sodium sulfate and concentrated. The crude product was purified by FC (20% ethyl acetate in hexanes) to give the title compound (3.02 g). Rf: 0.30 (20% ethyl acetate in hexane). The 1H NMR data was the same as that obtained from the product of Method A.
Step B: 4-(5-Benzyl-1-ethyl-(1H)-pyrazol-3-yl)-1-(t-butoxycarbonyl)piperidine (Higher Rf isomer) and 4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)-1-(t-butoxycarbonyl)piperidine (Lower Rf isomer)
Method A:
1-(1-(t-Butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione from Step A, from Method A or Method B, Step B3, (0.851 g, 2.46 mmol) in methanol (25 mL) was added over 10 min to a suspension of ethylhydrazine oxalate (0.444 g, 2.96 mmol) in methanol (5 mL) in a 60xc2x0 C. oil bath. After 15 h, the reaction was concentrated in vacuo and the residue was purified by repeated FC using a gradient of 50-100% ethyl acetate in hexanes to give first 4-(5-benzyl-1-ethyl-(1H)-pyrazol-3-yl)-1-(t-butoxycarbonyl)piperidine (0.148 g total) as the higher Rf product isomer and then the title compound (0.373 g total) as the lower Rf.
Higher Rf isomer: 1H NMR (500 MHz, CDCl3): xcex47.2-7.3 (m, 2 H), 7.3-7.4 (m, 1 H), 7.17 (d, J=7.5 Hz, 2 H), 5.77 (s, 1 H), 4.0-4.25 (m, 2 H), 3.97 (q, J=7.3 Hz, 2 H), 3.95 (s, 2 H), 2.7-2.9 (m, 2H), 2.76 (tt, J=11.3 and 3.8 Hz, 1 H), 1.92 (b rd, J=13 Hz, 1H), 1.5-1.65 (m, 2 H), 1.47 (s, 9 H), 1.29 (t, J=7.3 Hz, 3 H). Lower Rf isomer: 1H NMR (500 MHz, CDCl3): xcex47.25-7.4 (m, 3 H), 7.2 (m, 2 H), 5.72 (s, 1 H), 4.1-4.3 (m, 2 H), 4.08 (q, J=7.1 Hz, 2 H), 3.95 (s, 2 H), 2.7-2.9 (m, 2H), 2.66 (tt, J=11.3 and 3.8 Hz, 1 H), 1.82 (br d, J=12.8 Hz, 1 H), 1.4-1.6 (m, 2 H), 1.48 (s, 9 H), 1.47 (t, J=7.1 Hz, 3 H).
Method B:
Step B1: 1-(t-Butoxycarbonyl)4-hydroxymethylpiperidine
A solution of 25.03 g (109.2 mmole) N-Boc isonipecotic acid was dissolved in 200 mL THF and treated with 200 mL 1 M borane-tetrahydrofuran complex in THF, and the mixture was stirred overnight. The mixture was concentrated under vacuum, diluted with 750 mL ethyl acetate, and washed with 150 ML 1 N HCl (6xc3x97) and then saturated brine. The organic layer was dried over sodium sulfate and concentrated to give 24.3 g of crude product as a white solid. This was used as is in the next step.
1H NMR (500 MHz) xcex44.15 (br d, J=13.7 Hz, 2H), 3.52 (d, J=6.2 Hz, 2H), 2.69xcx9c2.75 (m, 2H), 1.71xcx9c1.75 (m, 2H), 1.62xcx9c1.70 (m, 1H), 1.47 (s, 9H), 1.12xcx9c1.21 (m, 2H),
Step B2: 1-(t-Butoxycarbonyl)-4-formylpiperidine
A mixture of 17.62 g (135.6 mmole) oxalyl chloride and 250 mL methylene chloride in a dry ice acetone bath. was treated with a solution of 21.19 g (271.2 mmole) DMSO in 150 mL methylene chloride over 20 minutes. After stirring for 20 minutes, a solution of 24.327 g 1-(t-butoxycarbonyl)-4-hydroxymethylpiperidine (from Step B1 above) in 150 mL methylene chloride was added over 1 h. After an additional 15 minutes, 57.17 (565 mmole) triethylamine in 150 mL methylene chloride was added over half an hour. The reaction mixture was allowed to warn up over night in the cooling bath. The reaction mixture was concentrated under vacuum to remove about 400 mL methylene chloride, and the residue was partitioned between 1 L ether and 300 mL water. To this was added 200 mL 1 N NaOH, the layers were separated, and the organic layer was washed with 150 mL 1 N NaOH (2xc3x97 ), water (3xc3x97), and saturated brine, dried over sodium sulfate, and concentrated to give 22.562 g crude product. FC (10xcx9c60% ethyl acetate in hexanes) gave 20.58 g title compound as slightly yellowish oil.
RF: 0.29 (3:1 v/v hexanes/ethyl acetate). 1H NMR (500 MHz) xcex49.68 (d, J=0.7 Hz, 1H), 3.96xcx9c4.02 (m, 2H), 2.92xcx9c2.97 (m, 2H), 2.40xcx9c2.45 (m, 1H), 1.88xcx9c1.94 (m, 2H), 1.53xcx9c1.64 (m, 2H), 1.47 (s, 9H).
Step B3: 1-(t-Butoxycarbonyl)-4-(2,2-dibromoethen-1-yl)piperidine
A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150 mL methylene chloride was added dropwise with stirring to a solution of 76.895 g (293.2 mmole) triphenyiphosphine in 150 mL methylene chloride in a 1-L rb flask with ice bath cooling over 1.75 h. After 40 minutes, a solution of 15.631 g (73.29 mmole) 1-(t-butoxycarbonyl)-4-formylpiperidine (from Step B2 above) in 100 mL methylene chloride was added to the resulting brown suspension with stirring and cooling over 40 minutes. After one hour, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL methylene chloride and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes until the total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5% sodium bicarbonate, 300 mL water (2xc3x97), and 150 mL brine. The organic layer was dried over sodium sulfate and concentrated under vacuum to give 53.5 g crude product as a yellowish solid. Flash chromatography (FC) on 250 g silica gel (0xcx9c15% ethyl acetate in hexanes) gave 21.595 g title compound as a white solid.
Rf: 0.57 (15% ethyl acetate in hexanes). 1H NMR (500 MHz) xcex46.25 (d, J=8.9 Hz, 1H), 4.04xcx9c4.12 (m, 2H), 2.75xcx9c2.83 (m, 2H), 2.42xcx9c2.50 (m, 1H), 1.69xcx9c1.75 (m, 2H), 1.47 (s, 9H), 1.29xcx9c1.37 (m, 2H).
Step B4: 1-(t-Butoxycarbonyl)-4-(2-tributylstannylethyn-1-yl)piperidine
A mixture of 23.199 g (62.85 mmole) 1-(t-butoxycarbonyl)-4-(2,2-dibromoethen-1-yl)piperidine (prepared as in Step B3 above) and 600 mL anhydrous THF was cooled with dry ice acetone bath under nitrogen. To this mixture was added 88 mL of a 1.6 M butyl lithium solution in hexanes dropwise with stirring and cooling over 50 minutes. After one hour, the flask was transferred into an ice bath. After another hour, a solution of 28.64 g (87.99 mmole) tributyltin chloride in 100 mL THF was added with stirring and cooling over 35 minutes. After three h, the mixture was concentrated under vacuum to remove some THF, and the residue was partitioned between 600 mL ice water and 800 mL ether. The organic layer was washed with 200 mL of water (1xc3x97), 2% sodium bicarbonate (1xc3x97), water (2xc3x97), and saturated brine (1xc3x97), dried over sodium sulfate and concentrated under vacuum to give 30.104 g crude product as a green-yellowish liquid. FC on 275 g silica gel using cold 2.5xcx9c15% ethyl acetate in hexanes as quickly as possible to give 27.115 g title compound as a colorless liquid.
Rf: 0.45 (10% ethyl acetate in hexanes). 1H NMR (500 MHz) xcex43.63xcx9c3.67 (m, 2H), 3.25xcx9c3.30 (m, 2H), 2.64xcx9c2.69 (m, 1H), 1.74xcx9c1.79 (m, 2H), 1.54xcx9c1.64 (m, 8H), 1.47 (s, 9H), 1.32xcx9c1.39 (m, 6H), 0.96xcx9c0.99 (m, 6H), 0.92 (t, J=7.3 Hz, 9H).
Step B5: 4-(1-(t-Butoxycarbonyl)piperidin-4-yl)-1-phenylbutan-2-on-3-yne
To a mixture of 1.727 g (3.466 mmole) 1-(t-butoxycarbonyl)-4-(2-tributyl-stannylethyn-1-yl)piperidine (prepared in Step B4 above) in 18 mL 1,2-dichloroethane was added 0.536 g (3.466 mmole) phenylacetyl chloride and 50 mg dichlorobis-(triphenylphosphine)palladium (II). The mixture was refluxed under nitrogen for 2 h, then concentrated under vacuum. Purification of the residue on silica gel (5xcx9c35% ethyl acetate in hexanes) gave 0.784 g title compound as a yellow oil.
Rf: 0.27 (20% ethyl acetate in hexanes). 1H NMR (500 MHz) xcex47.34xcx9c7.38 (m, 2H), 7.28xcx9c7.32 (m, 1H), 7.24xcx9c7.27 (m, 2H), 3.82 (s, 2H), 3.49xcx9c3.54 (m, 2H), 3.17xcx9c3.23 (m, 2H), 2.68xcx9c2.73 (m, 1H), 1.72xcx9c1.77 (m, 2H), 1.51xcx9c1.57 (m, 2H), 1.47 (s, 9H).
Tetrakis(triphenylphosphine)palladium gave a similar result.
Step B6: 4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)-1-(tert-butoxycarbonyl)piperidine
Heating 1.204 g (3.677 mmole) 4-(1-(t-butoxycarbonyl)piperidin-4-yl)-1-phenylbutan-2-on-3-yne (prepared in Step B5 above) with 0.662 g (4.413 mmole) ethylhydrazine oxalate and 1.252 g (9.687 mmole) DIEA in 20 mL ethanol over night gave an 8:1 ratio of the title compound and its isomer 4-(5-benzyl-1-ethyl-(1H)-pyrazol-3-yl)-1-(tert-butoxycarbonyl)piperidine. Use of ethylhydrazine free base gave even more favorable ratios of the desired title compound. The desired isomer can be isolated by recrystallization using hexanes or by silica gel chromatography using 5xcx9c10% acetonitrile in methylene chloride in addition to the procedure described in Method A above.
Step C: 4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidine di-TFA salt
To a solution of 4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)-1-(t-butoxycarbonyl)piperidine from Step B (lower Rf isomer) (0.373 g, 1.01 mmol) and anisole (0.219 mL, 2.02 mmol) in methylene chloride (15 mL) was added trifluoroacetic acid (1.555 mL, 20.2 mmol). The reaction was stirred at rt for 2.5 h and then concentrated. The residue was purified on preparative reverse-phase HPLC using 9.4xc3x97250 mm Semi-preparative Zorbax SB-C18 column with 17.5-35% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 6.05 mL per minute to give the title di-TFA salt compound as an oil. When a mixture of isomers from Step B is used, separation is also possible at this step with the above Prep HPLC conditions in which the title isomer elutes prior to 4-(5-benzyl-1-ethyl-(1H)-pyrazol-3-yl)piperidine.
Step A: 4-(3-Benzyl-(1H)-pyrazol-5-yl)-1-(t-butoxycarbonyl)piperidine TFA salt
A solution of 1-(1-(t-butoxycarbonyl)piperidin-4-yl)-4-phenyl-butane-1,3-dione from Procedure 1, Step A (30 mg, 0.087 mmol), hydrazine di-hydrochloride (10.9 mg, 0.1 mmol) and DIPEA (0.045 mL, 0.25 mmol) in methanol (1 mL) was heated at 50xc2x0 C. for 16 h. The volatiles were then removed under reduced pressure. Purification of the residue was done on preparative reverse-phase HPLC using a 9.4xc3x97250 mm Semi-preparative Zorbax SB-C18 column with 35-50% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min to give the title compound (45.2 mg) as a gel.
Step B: 4-(3-Benzyl-(1H)-pyrazol-5-yl)piperidine di-TFA salt
To a solution of 4-(3-benzyl-(1H-pyrazol-5-yl))-1-(t-butoxycarbonyl)piperidine TFA salt (from Step A) in methylene chloride (1.5 mL) was added anisole (0.017 mL) and TFA (0.230 mL). After several h at rt, volatiles were removed under reduced pressure. Purification of the residue was done by preparative reverse-phase HPLC using a 9.4xc3x97250 mm Semi-preparative Zorbax SB-C18 column with a 15-25% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 6.0 mL per minute to give the title compound (40.7 mg) as a gel.
Step A: 4-Phenylbutyl Bromide
To a solution of 4-phenyl-1-butanol (21.75 g) in acetonitrile (300 mL) was added triphenylphosphine dibromide (67.23 g) in portions with stirring over 10 min. After stirring over night under nitrogen, methanol (4 mL) was added and after 1.5 h, the solvent was removed under reduced pressure. Hexanes (200 mL) and xcx9c75 g silica gel were added to the residue and the mixture was filtered and the filter cake was eluted with hexanes. The clear filtrate was concentrated to give 32.8 g of clear colorless liquid. This product was again eluted through silica gel using 1.5 L hexanes to give the title compound (24.7 g) as a colorless liquid.
1H NMR (500 MHz, CDCl3): xcex47.28-7.32 (m, 2 H), 7.20-7.23 (m, 3 H), 3.44 (t, J=6.8 Hz, 2 H), 2.67 (t, J=7.6 Hz, 2 H), 1.93-1.89 (m, 2H), 1.77-1.84 (m, 2 H).
Step B: (4-Phenylbut-1-yl)triphenylphosphonium bromide
A solution of 4-phenylbutyl bromide from the Step A (24.7 g) and triphenylphosphine (19.00 g) in toluene (100 mL) was heated at 120-130xc2x0 C. for 3 days. The reaction was cooled to rt and the solid precipitate was collected by filtration, washed with toluene and air dried. The solid was dissolved in a 2:1 mixture of water and acetonitrile and gave the title compound (30.6 g) as a white solid after lyopholization.
1H NMR (500 MHz, CD3OD): xcex47.84-7.89 (m, 2 H), 7.71-7.81 (m, 15 H), 7.20-7.23 (m, 1 H), 7.11-7.15 (m, 2 H), 3.37-3.43 (m, 2 H), 2.66 (t, J=7.5 Hz, 2 H), 1.87 (tt, J=7.5 and 7.3 Hz, 2 H), 1.63-1.70 (m, 2 H).
Step C: 1-Benzyl-4-(4-phenylbutylidene)piperidine
A 0.62M solution of potassium bis(trimethylsilyl)amide in THF (180 mL, 112 mmol) in toluene (250 mL) was added to a mixture of (4-phenylbut-1-yl)triphenylphosphonium bromide from Step B (53 g) in toluene (250 mL) in an ice bath over 15 min with stirring under nitrogen. After stirring for a further 15 min, a solution of 1-benzyl-4-piperidone (16.9 g) in toluene (100 mL) was added over 30 min with stirring. The reaction mixture was allowed to warm to rt over 15 h. The reaction mixture was then poured into cold 1N HCl (400 mL) and the layers were separated. The organic layer was extracted with two more portions of 1N HCl. The combined cloudy HCl solution and an oil layer in between were washed with toluene (200 mL) before the aqueous layer was basified by the addition of potassium hydroxide (30 g). The aqueous layer was extracted with ether (3xc3x97150 mL) and the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by FC (10-15% ethyl acetate in hexanes having 4% (v/v) TEA) to give the title compound (16 g) as a colorless oil.
Rf: 0.47 (20% ethyl acetate in hexanes having 4% (v/v) TEA). 1H NMR (500 MHz, CDCl3): xcex47.26-7.38 (m, 7 H), 7.18-7.21 (m, 3 H), 5.18 (t, J=7.4 Hz, 1 H), 3.54 (s, 2 H), 2.61-2.64 (m, 2 H), 2.42-2.49 (m, 4 H), 2.22-2.27 (m, 4 H), 2.02-2.07 (m, 2 H), 1.65-1.71 (m, 2 H).
Step D: 1-(1-Benzylpiperidin-4-yl)-4-phenylbutan-1-one
To a solution of 4-(4-phenylbutylidene)-1-benzylpiperidine from Step C (4.37 g) in anhydrous ether (150 mL) under nitrogen with stirring was add 1M borane solution in THF (45 mL). The reaction was stirred for 3 h when water (2 mL) was added dropwise. The mixture was stirred a further 30 min and was then cooled in an ice bath. A solution of chromic anhydride (2.5 g), concentrated sulfuric acid (5.44 mL) and water (125 mL) was added dropwise with vigorous magnetic stirring over 5 min. After another 5 min, the ice bath was removed. After 1.5 h at rt, 0.5N sodium hydroxide and ether (400 mL each) were added and the mixture was stirred until the residue dissolved. The layers were separated and the aqueous layer was extracted twice with ether. The combined ether layers were washed with an aqueous EDTA solution, water and brine (100 mL each), dried over sodium sulfate and concentrated under reduced-pressure to give a colorless gel. Flash chromatography on silica gel with 30-50% ethyl acetate in hexanes with 3% (v/v) TEA gave the title compound (1 g) as a colorless gel. Rf: 0.43 (30% ethyl acetate in hexanes with 3% (v/v) TEA).
1H NMR (500 MHz, CDCl3): xcex47.25-7.33 (m, 7 H), 7.16-7.22 (m, 3 H), 3.51 (s, 2 H), 2.89-2.93 (m, 2 H), 2.63 (t, J=7.6 Hz, 2 H), 2.46 (t, J=7.2 Hz, 2 H), 2.38 (tt, J=11.5 and 3.9 Hz, 1 H), 1.99-2.03 (m, 2 H), 1.92 (tt, J=7.2 and 7.6 Hz, 2 H), 1.76-1.81 (m, 2 H), 1.65-1.72 (m, 2 H).
Step E: 1-(1-Benzylpiperidin-4-yl)-2-formyl-4-phenylbutan-1-one
To a solution of potassium t-butoxide (0.673 g) in THF (20 mL) under nitrogen and cooled in an ice bath was added a solution of 1-(1-benzylpiperidin-4-yl)-4-phenylbutan-1-one from Step D (0.71 g) and methyl formate (3.76 mL) in THF (12 mL) over 5 minute. The reaction was stirred for 15 min before being allowed to warm to rt for 2 h. The reaction was poured into water and extracted with ether (4xc3x97100 mL), methylene chloride (100 mL), and THF (100 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrate under reduced pressure. The crude product was purified by FC on silica gel eluting with 5 and 20% methanol in ethyl acetate with 4% TEA to afford the title compound (0.8 g). 1H NMR (500 MHz, CDCl3) showed a 3:1 ratio of enol (xcex48.54 ppm) and aldehyde (xcex49.54 ppm) forms. Other signals from the two forms were only partially resolved. The title compound had a retention time of 9.47 min on a Zorbax SB-C18 column (4.6xc3x9775 mm) eluting with 20-100% gradient of acetonitrile in water with 0.1% TFA over 10 min at 1 mL per min.
Step F: 4-(4-(2-Phenyleth-1-yl)-1-ethyl-(1H)-pyrazol-5-yl)-1-benzylpiperidine
di-TFA salt A solution of 1-(1-benzylpiperidin-4-yl)-2-formyl-4-phenyl-1-butanone from Step E (76.5 mg) and ethylhydrazine oxalate (45 mg) in methanol (4 mL) was heated at 45xc2x0 C. for 15.5 h. The solvent was removed under reduced pressure. The residue was purified by preparative reverse-phase IHPLC using a 9.4xc3x97250 mm Semi-preparative Zorbax SB-C18 column with 30-50% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 7.1 mL per min to give the title compound (45 mg) as the faster-eluting, minor isomer.
1H NMR (500 MHz, CD3OD): xcex47.46-7.52 (m, 5 H), 7.37 (s, 1 H), 7.21-7.24 (m, 2 H), 7.12-7.15 (m, 3 H), 4.32 (s, 2 H), 4.17 (q, J=7.2 Hz, 2 H), 3.53 (br d, J=12.4 Hz, 2 H), 3.06-3.12 (m, 3 H), 2.79-2.88 (m, 4 H), 2.10-2.20 (m, 2 H), 1.78 (br d, J=14.2 Hz, 2 H), 1.34 (t, J=7.2 Hz, 3 H). The isomeric assignment was confirmed by a NOESY spectrum. HPLC/MS (ESI): m/z 374.3 (M+1), 2.51 min.
Step G: 4-(4-(2-Phenyleth-1-yl)-1-ethyl-(1H)-pyrazol-5-yl)piperidine di-TFA salt
A mixture of ammonium formate (119 mg), 20% Pd(OH)2/C (5 mg) and 4-(4-(2-phenylethyl)-1-ethyl-(1H-pyrazol-5-yl))-1-benzylpiperidine di-TFA salt from Step F in methanol (2 mL) was heated at 60xc2x0 C. for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by preparative reverse-phase HPLC using a 9.4xc3x97250 mm Semi-preparative Zorbax SB-C18 column with 20-35% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 6.25 mL per min to give the title compound as the di-TFA salt (25 mg) as a gel.
1H NMR (500 MHz, CD3OD): xcex47.40 (s, 1 H), 7.22-7.25 (m, 2 H), 7.13-7.17 (m, 3 H), 4.20 (q, J=7.3 Hz, 2 H), 3.42-3.46 (m, 2 H), 3.05-3.15 (m, 3 H), 2.83-2.90 (m, 4 H), 2.04-2.14 (m, 2 H), 1.74-1.79 (m, 2 H), 1.36 (t, J=7.4 Hz, 3 H). The isomer assignment was confirmed by an NOE difference spectrum.
The title compound was prepared using essentially the same procedure as that described in Procedure 1, but substituting methyl 4-fluorophenylacetate for methyl phenylacetate in Step A, Method B, Step B3.
The title compound was prepared using essentially the same procedure as that described in Procedure 1, but substituting methyl 3,4-difluorophenylacetate for methyl phenylacetate in Step A, Method B.
Step A: (1-t-Butoxycarbonylpiperidin-4-yl)acetaldehyde
A solution of oxalyl chloride (1.23 mL, 14.1 mmol) in methylene chloride (50 mL) was cooled to xe2x88x9278xc2x0 C. DMSO (2.0 mL, 28.3 mmol), was added slowly via syringe. After 10 min, 4-(2-hydroxyeth-1-yl)-1-t-butoxycarbonylpiperidine (2.7 g, 11.8 mmol) in methylene chloride (15 mL) was added. The cold mixture was stirred for an additional 20 min then TEA (8.2 mL, 59 mmol) was added. The mixture was warmed to rt and stirred for 1.5 h, then diluted with methylene chloride (300 mL). The organic phase was washed with 1M sodium hydroxide, dried over sodium sulfate and concentrated. FC (125 g silica, 2.5/1 hexanes/ethyl acetate) afforded the title compound (2.25 g).
1H NMR (300 MHz, CDCl3): xcex41.1-1.2 (m, 2 H), 1.45 (s, 9 H), 1.65-1.75 (m, 2 H), 1.99-2.13 (m, 1 H), 2.38-2.4 (d, 2 H), 2.65-2.8 (m, 2 H), 4.03-4.15 (m, 2H), 9.78 (s, 1 H)
Step B: 4-(Prop-2-en-1-yl)-1-t-butoxycarbonylpiperidine
A solution of methyltriphenylphosphonium bromide (5.3 g, 14.8 mmol) in THF (50 mL) was cooled to 0xc2x0 C. under nitrogen. Potassium hexamethyl disilazide (27.7 mL, 0.5M toluene solution, 13.9 mmol) was added and the mixture was stirred for 30 min. A solution of (1-t-butoxycarbonylpiperidin-4-yl)acetaldehyde from Step A (2.25 g, 9.9 mmol) in THF (10 mL) was added and the mixture was warmed to rt. After 30 min, the reaction was complete by tlc analysis. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine (100 mL each). The organic phase was dried over sodium sulfate and concentrated to give an oil which was purified by FC (75 g silica, 10/1 hexane/ethyl acetate) to afford the title compound (1.61 g).
1H NMR (300 MHz, CDCl3): xcex41.03-1.18 (m, 2 H), 1.45 (s, 9 H), 1.4-1.5 (m, 1 H), 1.6-1.7 (m, 2 H), 1.99-2.13 (t, 1 H), 2.62-2.75 (m, 2 H), 4.03-4.15 (m, 2H), 4.98-5.12 (m, 2 H), 5.7-5.83 (m, 1 H).
Step C: 4-Bromobenzofurazan
To a solution of 2,6-dibromoaniline (10 g, 40 mmol) in glacial acetic acid (160 mL) was added 30% hydrogen peroxide (30 mL). The mixture was left for 48 h at which point crystals had precipitated. The crystals were collected by filtration, washed with acetic acid and water then dried under high vacuum to give 2,6-dibromonitrosobenzene (6.24 g). This material (2.6 g, 10 mmol) was dissolved in DMSO (25 mL) along with sodium azide (650 mg, 10 mmol). The mixture was heated to 100xc2x0 C. for 1 h then cooled to rt and diluted with ethyl acetate and water. The layers were separated and the organic phase was washed with water and brine, then dried over sodium sulfate and concentrated. FC (75 g silica, 10/1 hexane/ethyl acetate) afforded the title compound (1.7 g).
1H NMR (300 MHz, CDCl3): xcex47.25-7.35 (dd, 1 H), 7.6-7.65 (d, 1 H), 7.78-7.82 (d, 1 H)
Step D: 4-(3-(Benzofurazan-4-yl)prop-1-yl)piperidine hydrochloride
A solution of 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidine from Step B (330 mg, 1.46 mmol) in dry THF (0.5 mL) was cooled to 0xc2x0 C. and a solution of 9-BBN (3.2 mL, 0.5 M in THF, 1.61 mmol) was added. The mixture was warmed to rt and stirred for 5 h. Potassium carbonate (405 mg, 2.93 mmol), 1,2-bis(diphenylphosphino)-ferrocenyl palladium dichloride (60 mg, 0.073 mmol) and 4-bromobenzofurazan (from Step C) (292 mg, 1.46 mmol) were added followed by dry DMF (5 mL). The resulting mixture was heated to 55xc2x0 C. overnight then diluted with ethyl acetate. The solution was washed with water (3xc3x97) and brine, then dried over sodium sulfate and concentrated. FC (15 g silica, 5/1 hexane/ethyl acetate) afforded the title Boc derivative. Heating in 1% conc. HCl/methanol at 50xc2x0 C. for 2 h followed by removal of solvent and drying under vacuum afforded the title compound as the hydrochloride (155 mg).
1H NMR (300 MHz, CD3OD): xcex41.31-1.42 (m, 4 H), 1.6-1.75 (m, 1 H), 1.84-2.0 (m, 4 H), 2.9-3.1 (m, 4 H), 3.3-3.4 (m, 2 H), 7.25-7.3 (d, 1 H), 7.4-7.5 (dd, 1 H), 7.7-7.75 (d, 1 H).
Using essentially the same methods as in Procedure 5, but substituting 2,5-dibromoaniline for 2,6-dibromoaniline in Step C, the title compound was prepared.
Starting with 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidine from Procedure 5, Step B (475 mg, 2.1 mmol) and using essentially the same methods as in Procedure 5, Step D, but substituting 4-bromobenzonitrile (382 mg, 2.1 mmol), the title compound (337 mg) was obtained as the hydrochloride.
1H NMR (300 MHz, CD3OD). xcex41.31-1.42 (m, 4 H), 1.58-1.75 (m, 5 H), 1.9-2.1 (m, 2 H), 2.67-2.77 (t, 2 H), 2.9-3.0 (m, 2 H), 3.3-3.4 (m, 2 H), 7.35-7.4 (d, 2 H), 7.6-7.63 (d, 2 H).
Starting with 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidine from Procedure 5, Step B and using essentially the same methods as in Procedure 5, Step D, but substituting 4-bromo-2-fluorobenzonitrile, the title compound was obtained as the hydrochloride.
Starting with 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidine (from Procedure 5, Step B) and using essentially the same methods as in Procedure 5, Step D, but substituting 4-bromofluorobenzene, the title compound was obtained as the hydrochloride.
Step A: 1-(t-Butoxycarbonyl)-4-(3-(quinolin-3-yl)propyl)piperidine
A solution of 1-(t-butoxycarbonyl)-4-(prop-2-en-1-yl)piperidine (from Procedure 5, Step B) (260 mg, 1.15 mmol) in THF (3 mL) under argon was treated with 0.5M 9-BBN solution in THF (2.30 mL, 1.15 mmol). The resulting mixture was stirred at rt for 2 h, then treated with sodium methoxide (68 mg, 1.25 mmol). The resulting mixture was stirred until it was homogeneous (xcx9c15 min) and then was treated with 3-(bromo) quinoline (0.155 mL, 1.15 mmol) and [1,1xe2x80x2-bis(triphenylphosphino)ferrocene)dichloropalladium.methylene chloride (41 mg, 0.05 mmol). The resulting mixture was heated at reflux for 30 min, cooled and quenched with 1N NaOH (20 mL). The quenched reaction was extracted with 2xc3x9750 mL of ether; the extracts were dried over magnesium sulfate, combined and concentrated. FC (15 g of silica gel, 4:1 v/v hexanes/ethyl acetate) afforded the title compound (240 mg).
1H NMR (300 MHz, CDCl3): xcex41.00-1.16 (m, 2 H), 1.25-1.40 (m, 2 H), 1.45 (s, 9 H), 1.60-1.80 (m, 5 H), 2.62-2.72 (m, 2 H), 2.79 (t, J=7.8, 2 H), 4.06 (br s, 2 H), 7.52 (m, 1 H), 7.66 (m, 1 H), 7.76 (dd, J=8.0, 1.6, 1 H), 7.91 (d, J=1.6, 1 H), 8.77 (d, J=2.2, 1 H).
Step B: 4-(3-(Quinolin-3-yl)propyl)piperidine di-hydrochloride salt
A solution of 1-(t-butoxycarbonyl)-4-(3-(quinolin-3-yl)propyl)piperidine from Step A (240 mg, 0.68 mmol) in 1M HCl solution (8 mL) in methanol was stirred at rt for 48 h. The solution was concentrated and the residue crystallized from ethyl acetate to afford the title compound (182 mg),
1H NMR (500 MHz, CD3OD): xcex41.37-1.49 (m, 4 H), 1.67-1.74 (m, 2 H), 1.85-1.91 (m, 2H), 1.99 (app d, J=13.5 Hz, 2 H), 2.99 (app t, J=11.5 Hz, 2 H), 3.05 (t, J=8.0 Hz, 2H), 3.38 (app d, J=12.5 Hz, 1 H), 7.97 (t, J=7.0 Hz, 1 H), 8.13 (dt. J=1.0 and 7.0 Hz, 1H), 8.24 (d, J=8.5 Hz, 1 H), 8.31 (d, J=8.0 Hz, 1 H), 9.10 (s, 1 H), 9.21 (d, J=1.0 Hz, 1 H).
Step A: 1-(t-Butoxycarbonyl)-4-(3-(2-pyridyl)propyl)piperidine
The title compound was prepared using a procedure analogous to that described in Procedure 10, Step A, substituting (2-bromo)pyridine for (3-bromo)quinoline. FC (4:1 v/v hexanes/ethyl acetate followed by 3:2 v/v hexanes/ethyl acetate) provided the title compound (135 mg, 48%).
1H NMR (500 MHz, CDCl3): xcex41.05-1.81 (m, 10 H), 1.46 (s, 9 H), 2.67-2.82 (m, 2 H), 3.65 (m, 1 H), 4.08-4.16 (m, 2 H), 7.14-7.18 (m, 2 H), 7.63 (m, 1 H), 8.54 (d, J=4.4 Hz, 1 H). HPLC/MS (ESI): m/z 304 (M+1).
Step B: 4-(3-(2-Pyridyl)propyl)piperidine di-TFA salt
To a solution of 1-(t-butoxycarbonyl)-4-(3-(2-pyridyl)propyl)piperidine (from Step A) (128 mg, 0.42 mmol) in methylene chloride (1 mL) was added TFA (1 mL). After stirring for 2 h at rt, the reaction was concentrated to give the title compound (36 mg).
1H NMR (500 MHz, CDCl3): xcex41.22-1.46 (m, 5 H), 1.73-1.79 (m, 4 H), 2.68 (t, J=11.8 Hz, 2 H), 2.78 (t, J=7.8 Hz, 2 H), 3.19 (d, J=11.8 Hz, 2 H), 5.32 (br s, 1 H), 7.09-7.15 (m, 2 H), 7.59 (t, J 7.7 Hz, 2 H), 8.52 (d, J=4.6 Hz, 1 H).
Step A: 1-(t-Butoxycarbonyl)-4-(3,3-dibromoprop-2-en-1-yl)piperidine
To a solution of carbon tetrabromide (286 mg, 0.86 mmol) in methylene chloride (4 mL) at xe2x88x9210xc2x0 C. was added triphenylphosphine (339 mg, 1.29 mmol). After 10 min, a solution of ((1-t-butoxycarbonyl)piperidin-4-yl)acetaldehyde (from Procedure 5, Step A) (98 mg, 0.43 mmol) and TEA (0.060 mL, 0.43 mmol) in methylene chloride (2 mL) was added. After stirring at rt for 2 h, the reaction mixture was concentrated. The residue was purified by FC (9:1 v/v hexanes/ethyl acetate followed by 1:1 v/v hexanes/ethyl acetate) to give the title compound (118 mg).
1H NMR (500 MHz, CDCl3): xcex41.14-1.22 (m, 2 H), 1.47 (s, 9 H), 1.57-1.60 (m, 1 H), 1.67 (br d, J=12.6 Hz, 2H), 2.08 (t, J=7.1 Hz, 2 H), 2.70 (t, J=12.7 Hz, 2 H), 4.10 (br d, J=12.6 Hz, 2 H), 6.42 (t, J=7.4 Hz, 1 H).
Step B: 1-(t-Butoxycarbonyl)-4-(prop-2-yn-1-yl)piperidine
To a solution of 118 mg (0.31 mmol) of 1-(t-butoxycarbonyl)-4-(3,3-dibromoprop-2-en-1-yl)piperidine from Step A in THF (4 mL) at xe2x88x9278xc2x0 C. was added a 2.5M solution of n-butyl lithium (0.370 mL, 0.92 mmol). After stirring at xe2x88x9278xc2x0 C. for 45 min, the reaction mixture was quenched with sat""d ammonium chloride (4 mL) and diluted with ether (25 mL). After separating the phases, the aqueous layer was extracted with ether. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by FC (4:1 v/v hexanes/ether) to give the title compound (55 mg).
1H NMR (500 MHz, CDCl3): xcex41.18-1.26 (m, 2 H), 1.47 (s, 9 H), 1.60-1.67 (m, 1 H), 1.77 (br d, J=13.2 Hz, 2 H), 1.99 (t, J=2.6 Hz, 1 H), 2.16 (dd, J=6.6 Hz, 2.5, 2 H), 2.68-2.74 (m, 2 H), 4.12 (br d, J=13.0 Hz, 2 H).
Step C: 1-(t-Butoxycarbonyl)-4-(3-((4-trifluoromethyl)pyrimidin-2-yl)prop-2-yn-1-yl)piperidine
To a solution of 1-(t-butoxycarbonyl)-4-(prop-2-yn-1-yl)piperidine from Step B (86 mg, 0.39 mmol) in TEA (4 mL) under argon at 0xc2x0 C. was added 2-chloro-4-(trifluoromethyl)pyrimidine (0.070 mL, 0.58 mmol). After stirring at 0xc2x0 C. for 5 min, dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol), and copper iodide (4 mg, 0.02 mmol) was added and the reaction vessel was flushed with argon. After 3 h at 60xc2x0 C., the reaction mixture was cooled to rt and quenched with 1N sodium hydroxide (5 mL) and diluted with ether (25 mL). After separating the phases, the aqueous layer was extracted again with ether. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by FC (9:1 v/v hexanes/ethyl acetate followed by 2:1 v/v hexanes/ethyl acetate) to give the title compound (132 mg).
1H NMR (400 MHz, CDCl3): xcex41.26-1.33 (m, 2 H), 1.46 (s, 9 H), 1.80-1.88 (m, 3 H), 2.46 (d, J=6.4 Hz, 2 H), 1.99 (br t, J=11.2 Hz, 1 H), 4.10-4.40 (m, 2 H), 7.54 (d, J=5.0 Hz, 1 H), 8.94 (d, J=5.0 Hz, 1 H).
Step D: 1-(t-Butoxycarbonyl)-4-(3-((4-trifluoromethyl)pyrimidin-2-yl)prop-1-yl)piperidine
To a solution of 1-(t-butoxycarbonyl)-4-(3-((4-trifluoromethyl)pyrimidin-2-yl)prop-2-yn-1-yl)piperidine from Step C (130 mg) in methanol (4 mL) was added 10% palladium on carbon (15 mg). The mixture was hydrogenated using a Parr shaker set at 40 psi. After TLC indicated the absence of the starting material, the reaction was filtered through a 0.45 micron nylon membrane polypropylene filter and concentrated. FC (9:1 v/v hexanes/ethyl acetate followed by 2:1 v/v hexanes/ethyl acetate) of the residue afforded the title compound.
1H NMR (400 MHz, CDCl3): xcex41.04-1.15 (m, 2 H), 1.27-1.49 (m, 3 H), 1.46 (s, 9 H), 1.68 (br d, J=12.7 Hz, 2 H), 1.85-1.93 (m, 2 H), 2.68 (br t, J=12.1 Hz, 2 H), 3.05 (t, J=7.7 Hz, 2 H), 4.08(br d, J=11.5 Hz, 2 H), 7.47(d, J=5.0 Hz, 1 H), 8.92 (d, J=5.0 Hz, 1 H).
Step E: 4-(3-((4-Trifluoromethyl)pyrimidin-2-yl)prop-1-yl)piperidine
The title compound was prepared from 1-(t-butoxycarbonyl)-4-(3-((4-trifluoromethyl)pyrimidin-2-yl)prop-1-yl)piperidine (from Step D) (17 mg, 0.046 mmol) using a procedure analogous to that described in Procedure 10, Step B. FC (95:5:0.5 v/v/v methylene chloride/methanol/NH4OH) afforded the title compound (22 mg).
1H NMR (300 MHz, CDCl3): xcex41.21-3.45 (m, 15 H), 7.52 (d, J=5.0 Hz, 1 H), 8.95 (d, J=5.0 Hz, 1 H).
Step A: 4-Amino-1-t-butoxycarbonylpiperidine
1-t-Butoxycarbonylpiperidin-4-one (20 g, 100 mmol), benzylamine (11 mL, 100 mmol) and sodium triacetoxyborohydride (32 g, 150 mmol) were stirred together in 1,2-dichloroethane (400 mL) for 3 h. The resulting mixture was diluted with ethyl acetate (1 L) and washed with 1M aqueous sodium hydroxide (500 mL) followed by brine (500 mL). The organic phase was dried over sodium sulfate and concentrated to afford 4-N-benzylamino-1-t-butoxycarbonyl piperidine (30.1 g) as a viscous oil. The oil was dissolved in methanol (400 mL) and ammonium formate (39 g, 600 mmol) was added. The vessel was purged with nitrogen and 10% palladium-on carbon (6.5 g, 6 mmol) was added. The mixture was refluxed for 1 h and then filtered through celite and concentrated. Drying under vacuum afforded the title compound (20 g).
1H NMR (300 MHz, CDCl3): xcex41.15-1.3 (m, 2 H), 1.43 (s, 9 H), 1.7-1.9 (m, 4 H), 2.65-2.72 (m, 3 H), 3.95-4.1 (m, 2 H).
Step B: 4-(N-(Pyrimidin-2-yl)amino)-1-t-butoxycarbonylpiperidine
4-Amino-1-t-butoxycarbonylpiperidine from Step A, (1.9 g, 9.5 mmol), 2-chloropyrimidine (1.1 g, 9.5 mmol) and DIPEA (3.3 mL, 19 mmol) were combined in isopropanol (10 mL) and the mixture was refluxed for 24 h. The mixture was cooled, diluted with methylene chloride (100 mL) and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated. FC (60 g silica, 1/1 hexanes/ethyl acetate) afforded the title compound (0.97 g).
1H NMR (300 MHz, CDCl3): xcex41.31-1.45 (m, 2 H), 1.44 (s, 9 H), 2.0-2.1 (m, 2 H), 2.9-3.0 (m, 2 H), 3.9-4.1 (m, 3 H), 5.0-5.05 (m, 1 H), 6.5-6.58, (t, 1 H), 8.15-8.2 (d, 2 H).
Step C: 4-(N-(Pyrimidin-2-yl)-N-(allyl)amino)-1-t-butoxycarbonyl-piperidine
A solution of 4-(N-(pyrimidin-2-yl)amino)-1-t-butoxycarbonylpiperidine from Step B (528 mg, 1.9 mmol) in dry THF (5 mL) was cooled to xe2x88x9278xc2x0 C. and a solution of sodium hexamethyldisilazide (2.8 mL, 1.0 M in THF, 2.8 mmol) was added via syringe. The mixture was stirred cold for 20 min then allyl bromide (0.23 mL, 2.7 mmol) was added. The mixture was then warmed to rt and stirred for 1.5 h at which time TLC showed very little starting material. The solution was poured into sat""d ammonium chloride and methylene chloride. The layers were separated and the organic phase was dried over sodium sulfate and concentrated. FC (25 g silica, 4/1 hexanes/ethyl acetate) afforded the title compound (367 mg).
1H NMR (300 MHz, CDCl3): xcex41.45 (s, 9 H), 1.6-1.8 (m, 4 H), 2.75-2.85 (m, 2 H), 4.1-4.3 (m, 4 H), 4.74.8 (m, 1 H), 5.05-5.17 (m, 2 H), 5.92-5.98 (m, 1 H), 6.4-6.5 (t, 1 H), 8.3-8.35 (d, 2 H).
Step D: 4-(N-(Pyrimidin-2-yl)-N-(prop-1-yl)amino)piperidine di-hydrochloride salt
In a round bottom flask purged with nitrogen 4-(N-(pyrimidin-2-yl)-4-N-(allyl)amino)-1-t-butoxylcarbonylpiperidine from Step C (461 mg, 1.45 mmol) was dissolved in methanol (4 mL) and 10% palladium on carbon (150 mg, 0.14 mmol) was added. The mixture was stirred under 1 atm of hydrogen using a balloon for 1.5 h. The mixture was filtered through celite and concentrated. FC (20 g silica, 3/1 hexanes/ethyl acetate) afforded 4-(N-(pyrimidin-2-yl)4-N-(prop-1-yl)amino)-1-t-butoxylcarbonylpiperidine.
1H NMR (400 MHz, CDCl3). xcex40.9-1.0 (t, 3H, J=7 Hz), 1.5 (s, 9 H), 1.6-1.8 (m, 6 H), 2.8-2.9 (m, 2 H), 3.33-3.4 (m, 2 H), 4.2-4.27 (m, 2 H), 4.7-4.8 (m, 1 H), 6.42-6.45 (t, 1 H), ), 8.3-8.35 (d, 2 H).
This material was dissolved in 2% conc. HCl/methanol and heated to 50xc2x0 C. for 2 h. Removal of solvent and drying under vacuum afforded the title compound as a white solid.
4-(3-(3,4-Difluorophenyl)prop-1-yl)piperidine hydrochloride salt
Starting with 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidine from Procedure 5, Step B and using essentially the same methods as in Procedure 5, Step D, but substituting 3,4-difluorobromobenzene, the title compound was obtained as the hydrochloride.
4-(5-Benzyl-1-(prop-1-yl)-(1H)-pyrazol-3-yl)piperidine di-hydrochloride salt (Higher Rf isomer) and 4-(3-benzyl-1-(prop-1-yl)-(1H)-pyrazol-5-yl)piperidine di-hydrochloride salt (Lower Rf isomer)
Using essentially the same methods as in Procedure 1, Step B-C, but substituting propylhydrazine for ethylhydrazine in Step B, the title compounds were prepared.
Step A: 1-(Benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-en-1-yl)piperidine
DIPEA (4.6 mL, 3.4 g, 26 mmol) was added to a solution of 4-(hydroxymethyl)piperidine (2.00 g, 17.4 mmol) dissolved in methylene chloride (20 mL). The solution was cooled in an ice bath and benzyl chloroformate (2.5 mL, 3.0 g, 18 mmol) was added dropwise over 10 min. After warming to rt and stirring for 96 h, the mixture was diluted with ethyl acetate (50 mL) and washed in succession with 25 mL each of saturated aq. sodium bicarbonate, 2N aq. HCl, saturated aq. sodium bicarbonate, and saturated aq. brine. The organic layer was dried (sodium sulfate), decanted, and evaporated to give 4.14 g of 1-(benzyloxycarbonyl)-4-(hydroxymethyl)piperidine.
1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (1.92 g, 4.53 mmol) was added to a solution of 1-(benzyloxycarbonyl)-4-(hydroxymethyl)piperidine (1.00 g, 4.01 mmol) in methylene chloride (20 mL) and the mixture was stirred at rt for 45 min. Ether (75 mL) and 1.3 N aq. NaOH (25 mL) were added and stirring was continued for 15 min. The mixture was transferred to a separatory funnel with additional ether (30 mL) and 1.3 N aq. NaOH (20 mL). The organic layer was separated, washed with saturated aq. brine (20 mL), dried (sodium sulfate), decanted, and evaporated to give 846 mg of 1-(benzyloxycarbonyl)4-piperidine carboxaldehyde as a colorless syrup.
Diethyl (2-oxo-2-phenylethyl)phosphonate (0.96 mL, 1.1 g, 4.4 mmol) was added in one portion to a stirred suspension of sodium hydride (60% oil dispersion, 158 mg, 3.95 mmol) in THF (20 mL). After 15 min. at rt, the clear solution was cooled in an ice bath and 1-(benzyloxycarbonyl)-4-piperidinecarboxaldehyde (840 mg, 3.40 mmol) was added in THF (1.0 mL) with additional THF (2xc3x971.0 mL) for rinsing. Stirring was continued for a total of 2 h, with slow warming to rt. The mixture was then partitioned between ether (120 mL) and 2.5 N aq. NaOH (60 mL). The organic layer was washed with saturated aq. brine (60 mL), dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 15-20% ethyl acetate in hexane, to give 0.95 g of the title compound as a colorless syrup.
1H NMR (400 MHz, CDCl3): xcex47.82 (d, J=8 Hz, 2 H), 7.57 (t, J=8 Hz, 1 H), 7.48 (t, J=8 Hz, 2 H), 7.39-7.29 (m, 5 H), 6.99 (dd, J=15, 6 Hz, 1 H), 6.87 (dd, J=15 and 1 Hz, 1 H), 5.15 (s, 2 H), 2.97-2.82 (m, 2 H), 2.50-2.39 (m, 1 H), 1.89-1.77 (m, 2 H), 1.54-1.39 (m, 2 H). MS (ESI): m/z 367 (M+NH3+H).
Step B: 2-(2-(1-(Benzyloxycarbonyl)piperidin-4-yl)ethyl)-2-phenyl-1,3-dithiolane
1-(Benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-en-1-yl)piperidine from Step A (0.95 g, 2.7 mmol) was hydrogenated using 5% Pd/C (10 mg) in 95% ethanol (20 mL) at atmospheric pressure. After 3.5 h, the mixture was filtered and the catalyst was washed with 95% ethanol. Evaporation of the filtrate gave 0.95 g of 1-(benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-yl)piperidine as a colorless syrup.
Boron trifluoride-acetic acid complex (BF3.2-CH3CO2H, 0.370 mL, 501 mg, 2.67 mmol) was added to a solution of 1,2-ethanedithiol (0.440 mL, 494 mg, 5.25 mmol) and (1-(benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-yl)piperidine (930 mg, 2.65 mmol) in methylene chloride (4.0 mL) at rt. After 6 h, the mixture was diluted with ether (50 mL) and washed with saturated aq. sodium bicarbonate (2xc3x9725 mL), 2.5 N aq. NaOH (25 mL), and saturated aq. brine (25 mL). The organic layer was dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 10% ethyl acetate in hexane, to give 1.05 g of the title compound as a colorless liquid.
1H NMR (400 MHz, CDCl3): xcex47.66 (d, J=8 Hz, 2 H), 7.38-7.26 (m, 7 H), 7.22 (t, J=8 Hz, 1 H), 5.10 (s, 2 H), 4.18-4.02 (m, 2 H), 3.41-3.32 (m, 2 H), 3.29-3.20 (m, 2 H), 2.79-2.62 (m, 2 H), 2.40-2.32 (m, 2 H), 1.65-1.54 (m, 2 H), 1.40-1.27 (m, 1 H), 1.24-1.16 (m, 2 H), 1.10-0.97 (m, 2 H); HPLC/MS (ESI): m/z 428 (M+H); HPLC: 4.21 min.
Step C: 1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-phenylprop-1-yl)piperidine
1,3-Dibromo-5,5-dimethylhydantoin (74 mg, 0.26 mmol) was stirred with methylene chloride (0.50 mL) at rt, and the suspension was then cooled in a dry ice/isopropanol bath. After 5 min., hydrogen fluoride.pyridine (70% HF, 0.18 mL) was added over 1 min. After 5 min., a solution of 2-(2-(1-(benzyloxycarbonyl)piperidin-4-yl)ethyl)-2-phenyl-1,3-dithiolane from Step B (100 mg, 0.234 mmol) in methylene chloride (0.20 mL) was added over 1 min. After 10 min, the reaction mixture was diluted into methylene chloride (25 mL) and washed with water (10 mL) containing sodium bisulfite (0.5 g). The organic layer was washed with saturated aq. sodium bicarbonate (2xc3x9710 mL) followed by saturated aq. brine (10 mL), dried (sodium sulfate), decanted, and evaporated to give 98 mg of colorless syrup. This material was combined with 195 mg of crude product from two similar reactions and purified by FC, eluting with 8% ethyl acetate in hexane, to give 247 mg of 1-(benzyloxycarbonyl)-4-(3,3-difluoro-3-phenylprop-1-yl)piperidine (Rf: 0.3 using 10% ethyl acetate in hexane) containing some residual impurity.
The partially purified 1-(benzyloxycarbonyl)-4-(3,3-difluoro-3-phenylprop-1-yl)piperidine (247 mg) was hydrogenated at atmospheric pressure in 95% ethanol (4.0 mL) containing 20% Pd(OH)2/C (60 mg). After 6 h, additional 20% Pd(OH)2/C (32 mg) was added and the hydrogenation was continued for another 16 h. The mixture was filtered and the catalyst was washed with 95% ethanol. Evaporation of the filtrate gave 164 mg of crude 4-(3,3-difluoro-3-phenylprop-1-yl)piperidine as a colorless syrup.
Di-t-butyl dicarbonate (178 mg, 0.816 mmol) was transferred with methylene chloride (2xc3x970.5 mL) to a solution of crude 4-(3,3-difluoro-3-phenylprop-1-yl)piperidine (164 mg) in methylene chloride (2.0 mL). After stirring at rt for 1 h, the solution was stored at xe2x88x9220xc2x0 C. for 48 h. The mixture was then diluted into ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (10 mL) followed by saturated aqueous brine (10 mL). The organic layer was dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 4-5% ethyl acetate in hexane to give the title compound as 112 mg of colorless syrup. Rf: 0.25 (5% ethyl acetate in hexane).
1H NMR (400 MHz, CDCl3): xcex47.50-7.40 (m, 5 H), 4.24-3.99 (m, 2 H), 2.64 (bt, J=12 Hz, 2 H), 2.14 (tm, J=16 Hz, 2 H), 1.62 (bd, J=12 Hz, 2 H), 1.45 (s, 9 H), 1.42-1.33 (m, 3 H), 1.13-1.00 (m, 2 H).
Step D: 4-(3,3-Difluoro-3-phenylprop-1-yl)piperidine
Trifluoroacetic acid (2.5 mL, 3.7 g, 32 mmol) was added dropwise to a solution of 1-(t-butoxycarbonyl)4-(3,3-difluoro-3-phenylprop-1-yl)piperidine from Step C (42 mg, 0.12 mmol) in methylene chloride (2.5 mL) at 0xc2x0 C. After 80 min., the solution was transferred using a double-ended needle to a rapidly stirred solution of sodium bicarbonate (5.0 g, 60 mmol) in water (50 mL). Ether (50 mL) and 2.5 N aq. NaOH (20 mL) were added, followed by solid brine to saturate the aqueous layer. The aqueous layer was separated and extracted with ether (50 mL). The organic layers were washed in succession with saturated aq. brine (20 mL), combined, dried (sodium sulfate), decanted, and evaporated to give the title compound as 27 mg of colorless oil.
1H NMR (400 MHz, CD3OD): xcex47.51-7.40 (m, 5 H), 2.98 (dm, J=12 Hz, 2 H), 2.53 (td, J=12 and 3 Hz, 2 H), 2.24-2.10 (m, 2 H), 1.65 (bd, J=12 Hz, 2 H), 1.42-1.26 (m, 3 H), 1.06 (qd, J=12 and 4 Hz, 2 H). HPLC/MS (ESI): m/z 240 (M+H); HPLC: 2.25 min.
Step A: 1-(t-Butoxycarbonyl)-4-(hydroxymethyl)piperidine
Di-t-butyl dicarbonate (4.69 g, 21.5 mmol) was transferred in methylene chloride (9 mL) over 10 min. to a solution of 4-(hydroxymethyl)piperidine (2.47 g, 21.4 mmol) in methylene chloride (16 mL). After stirring at rt for 1 h, the solution was diluted with ether (50 mL) and washed with 2 N aq. HCl, saturated aq. sodium bicarbonate, and saturated aq. brine (25 mL of each). The organic layer was dried (sodium sulfate), decanted, and evaporated to give 4.57 g of the title compound as a crystalline solid.
1H NMR (500 MHz, CD3OD): xcex44.08 (d, J=14 Hz, 2 H), 3.40 (d, J=6 Hz, 2 H), 2.81-2.67 (m, 2 H), 1.71 (d, J=13 Hz, 2 H), 1.67-1.58 (m, 1 H), 1.44 (s, 9 H), 1.09 (qd, J=12 and 4 Hz, 2 H).
Step B: 1-(t-Butoxycarbonyl)-4-(iodomethyl)piperidine
Methanesulfonyl chloride (4.10 mL, 6.07 g, 52.9 mmol) was added dropwise to a solution of 1-(t-butoxycarbonyl)-4-(hydroxymethyl)piperidine from Step A (10.0 g, 46.4 mmol) and triethylamine (9.80 mL, 7.11 g, 70.3 mmol) in methylene chloride (140 mL) at 5-8xc2x0 C. After 1 h, the mixture was diluted with ethyl acetate (400 mL) and washed with water (200 mL). The aqueous layer was extracted with ethyl acetate (2xc3x97150 mL) and the combined organic layers were washed with 1 N aq. HCl (200 mL), saturated aq. sodium bicarbonate (200 mL), and saturated aq. brine (200 mL). The organic layer was dried (sodium sulfate), decanted, and evaporated to give 13.58 g of 1-(t-butoxycarbonyl)piperidin-4-yl methanesulfonate as a pale yellow solid.
A mixture of 1-(t-butoxycarbonyl)piperidin-4-yl methanesulfonate (13.58 g, 46.4 mmol) and sodium iodide (34.68 g, 232 mmol) in acetone (80 mL) was heated to reflux for 3 h. The mixture was partitioned between ether (350 mL) and water (350 mL). The organic layer was washed with saturated aq. brine (250 mL), and the aqueous layers were extracted in succession with ether (250 mL). The combined organic layers were dried (sodium sulfate), decanted, and evaporated to give the title compound (14.8 g) as a pale yellow oil.
1H NMR (500 MHz, CDCl3): xcex44.25-4.00 (m, 2 H), 3.12 (d, J=4 Hz, 2 H), 2.78-2.52 (m, 2 H), 1.85 (d, J=13 Hz, 2 H), 1.68-1.56 (m, 1 H), 1.48 (s, 9 H), 1.15 (qd, J=12 and 4 Hz, 2 H).
Step C: ((1-(t-Butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide
A solution of triphenylphosphine (6.63 g, 25.3 mmol) and 1-(t-butoxycarbonyl)-4-(iodomethyl)piperidine from Step B (7.96 g, 24.5 mmol) in acetonitrile (40 mL) was heated to reflux for 72 h. The solution was evaporated to give 13.35 g of white solid. A portion (12.34 g) of this material was dissolved in acetonitrile (25 mL) at 65xc2x0 C. Ethyl acetate (35 mL) was added and the mixture was allowed to cool slowly to rt and then to xe2x88x9220xc2x0 C. The supernatant was decanted, and the colorless crystals were washed with ethyl acetate (5xc3x975 mL) and dried under vacuum to give 9.25 g of the title compound.
1H NMR (500 MHz, CD3OD): xcex47.89 (t, J=8 Hz, 3 H), 7.86 (dd, J=12 and 8 Hz, 6 H), 7.76 (td, J=8 and 4 Hz, 6 H), 3.91 (bd, J=13 Hz, 2 H), 3.44 (dd, J=14 and 6 Hz, 2 H), 2.72-2.58 (m, 2 H), 2.08-1.96 (m, 1 H), 1.49 (bd, J=12 Hz, 2 H), 1.41 (s, 9 H), 1.43 (qd, J=13 and 4 Hz, 2 H).
Step D: Methyl (4-fluorobenzoyl)formate
Dimethyl oxalate (5.90 g, 50 mmol) was dissolved in THF (50 mL) and ether (50 mL) in a 3-neck round bottom flask fitted with a mechanical stirrer. The solution was stirred vigorously at xe2x88x9265xc2x0 C. as a 1.0 M THF solution of 4-fluorophenylmagnesium bromide (60 mL, 60 mmol) was added dropwise over 40 min. The mixture was stirred 30 min at xe2x88x9265xc2x0 C. and allowed to warm to xe2x88x9220xc2x0 C. over 30 min before being poured into 2N aq. HCl (50 mL) with stirring. The layers were separated and the aq. layer was extracted with ether (3xc3x9750 mL). The combined organic layers were washed with saturated aq. brine (2xc3x9750 mL), dried (sodium sulfate), decanted, and evaporated. The residue was dissolved in ethyl acetate, dried (sodium sulfate), filtered, and evaporated to give a yellow solid. The crude product was dissolved in warm hexane (25 mL), filtered, and cooled to xe2x88x9220xc2x0 C. Filtration followed by washing with cold hexane (15 mL) gave 4.95 g of the title compound as light tan crystals.
1H NMR (500 MHz, CDCl3): xcex48.11 (dd, J=9 and 5, Hz, 2 H), 7.21 (t, J=9 Hz, 2 H), 4.00 (s, 3 H).
Step E: Methyl difluoro(4-fluorophenyl)acetate
Methyl (4-fluorobenzoyl)formate from Step D (4.75 g, 26.1 mmol) was added to (diethylamino)sulfur trifluoride (7.0 mL, 8.5 g, 53 mmol). The mixture was stirred rapidly and an ice bath was used briefly to reduce the temperature to 15xc2x0 C. After the ice bath was removed, the reaction temperature rose to 48xc2x0 C. over 10 min and then slowly returned to rt. After a total of 2.75 h, the solution was carefully poured onto crushed ice (30 g) and the mixture was extracted with methylene chloride (2xc3x9725 mL). The organic layers were washed in succession with saturated aq. sodium bicarbonate (2xc3x9725 mL) and saturated aq. brine (10 mL), combined, dried (sodium sulfate) decanted, and evaporated. The residue was distilled to give the title compound as 4.16 g of light yellow liquid, B.P. 46-48xc2x0 C. (0.5 mm Hg).
1H NMR (500 MHz, CDCl3): xcex47.63 (dd, J=9, 5 Hz, 2 H), 7.16 (d, J=9 Hz, 2 H), 3.88 (s, 3 H).
Step F: 1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-en-1-yl)piperidine
A solution of methyl difluoro(4-fluorophenyl)acetate (2.04 g, 10.0 mmol) from Step E in methanol (10.0 mL) was cooled to xe2x88x9260xc2x0 C. Sodium borohydride (380 mg, 10.0 mmol) was added in 5 portions at 10 to 15 min. intervals. The mixture was cooled to xe2x88x9260 to xe2x88x9255xc2x0 C. prior to each addition and allowed to warm to xe2x88x9245xc2x0 C. following each addition. After the last addition, the mixture was stirred 1.25 h at xe2x88x9250 to xe2x88x9245xc2x0 C. The mixture was cooled to xe2x88x9260xc2x0 C. and quenched with 1 N aq. HCl (30 mL), with the temperature rising to xe2x88x9220xc2x0 C. near the end of the addition. After warming to 0xc2x0 C., the mixture was extracted with ether (3xc3x9720 mL). The combined ether layers were washed with water (2xc3x9720 mL), dried (sodium sulfate), decanted, and evaporated to give 1.95 g of crude 2,2-difluoro-2-(4-fluorophenyl)-1-methoxyethanol as a pale yellow oil.
A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (500 mg, 0,92 mmol) from Step C in THF (7.2 mL) was stirred at rt for 30 min. A 0.5 M toluene solution of potassium bis(trimethylsilyl)amide (1.8 mL, 0.90 mmol) was added over 3 min., giving an orange suspension. After 30 min., crude 2,2-difluoro-2-(4-fluorophenyl)-1-methoxyethanol (95 mg, 0.46 mmol) was added in THF (1.0 mL). After an additional 30 min, the mixture was quenched by the addition of saturated aq. NH4Cl (2 mL). The mixture was partitioned between ethyl acetate (50 mL) and water (75 mL), and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were washed in succession with saturated aq. brine (25 mL), dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 10% ether in hexane to give 117 mg of the title compound as a 95:5 mixture of cis and trans isomers, respectively.
1H NMR (500 MHz, CDCl3): xcex47.55 (dd, J=9 and 5 Hz, 2 H), 7.13 (t, J=9 Hz, 2 H), 5.76 (q, J=12 Hz, 1 H), 5.64 (dd, J=12 and 10 Hz, 1 H), 4.20-3.95 (m, 2 H), 2.80-2.54 (m, 3 H), 1.54 (bd, J=12 Hz, 2 H), 1.47 (s, 9 H), 1.26 (qd, J=12 and 4 Hz, 2 H).
Step G: 1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)propyl)piperidine
Potassium azodicarboxylate (695 mg, 3.58 mmol) was added to a solution of 1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-en-1-yl)piperidine from Step F (424 mg, 1.19 mmol) in methanol (3.3 mL). The mixture was stirred at rt as a 9.0 M solution of acetic acid in methanol (0.80 mL, 7.2 mmol) was added over 3 h using a syringe pump. After 30 min., a second portion of potassium azodicarboxylate (695 mg, 3.58 mmol) was added followed by the addition of 9.0 M acetic acid in methanol (0.80 mL, 7.2 mmol) over 3 h. After 20 min, a third portion of potassium azodicarboxylate (695 mg, 3.58 mmol) was added followed by the addition of 9.0 M acetic acid in methanol (0.80 mL, 7.2 mmol) over 3 h. After stirring for 20 h at rt, the mixture was diluted with ethyl acetate (80 mL), and washed with 2 N aq. HCl (40 mL), saturated aq. sodium bicarbonate (40 mL), and saturated aq. brine (40 mL). The organic layer was dried (sodium sulfate), decanted, and evaporated to give 417 mg of a mixture containing the title compound and 20-25% of unreduced 1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-en-1-yl)piperidine.
A portion (365 mg) of the crude mixture containing residual olefin was hydrogenated at atmospheric pressure for 16 h using iridium black (30 mg) in a mixture of t-butanol (24 mL) and ethyl acetate (2.4 mL). The mixture was filtered, the catalyst was washed with methanol, and the filtrate was evaporated to give 371 mg of the title compound as a pale yellow syrup. Rf: 0.2 (5% ethyl acetate in hexane).
1H NMR (500 MHz, CDCl3): xcex47.46 (dd, J=9 and 5 Hz, 2 H), 7.12 (t, J=9 Hz, 2 H), 4.18-4.00 (m, 2 H), 2.73-2.61 (m, 2 H), 2.14 (tm, J=16 Hz, 2 H), 1.64 (bd, J=12 Hz, 2 H), 1.46 (s, 9 H), 1.46-1.33 (m, 3 H), 1.08 (qd, J=12 and 4 Hz, 2 H).
Step H: 4-(3,3-Difluoro-3-(4-fluorophenyl)prop-1-yl)piperidine
1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-yl)piperidine from Step G (122 mg, 0.34 mmol) was dried by evaporation of a toluene solution at reduced pressure. The residue was dissolved in chloroform (7.6 mL) and iodotrimethylsilane (0.100 mL, 141 mg, 0.70 mmol) was added. After stirring 30 min at rt, the solution was poured into a mixture of saturated aqueous sodium bicarbonate (15 mL) and 2.5 N aq. NaOH (5 mL), and extracted with ether (50 mL). The organic layer was washed with saturated aq. brine (15 mL), dried (sodium sulfate), decanted, and evaporated to give the title compound as 88 mg of colorless oil.
1H NMR (500 MHz, CD3OD): xcex47.51 (dd, J=9 and 5 Hz, 2 H), 7.17 (t, J=9 Hz, 2 H), 2.98 (dm, J=12 Hz, 2 H), 2.52 (td, J=12, 3 Hz, 2 H), 2.17 (tm, J=16 Hz, 2 H), 1.65 (bd, J=13 Hz, 2 H), 1.42-1.26 (m, 3 H), 1.07 (qd, J=12 and 4 Hz, 2 H). HPLC/MS (ESI): m/z 258 (M+H); HPLC: 2.64 min.
Step A: 4-(2-hydroxyeth-1-yl)piperidine acetic acid salt
Combined 4-(2-hydroxyeth-1-yl)pyridine (25 g, 0.2 mol) and platinum oxide (1 g, 4.4 mmol) in 400 mL acetic acid. Placed under 45 psi hydrogen at 60xc2x0 C. for 24 h. Decanted, then filtered through Celite and removed the solvent to afford 38 g (100%) of the crude product, which was used without further purification.
Step B: 4-(2-hydroxyeth-1-yl)-1-tert-butoxycarbonylpiperidine
Dissolved sodium bicarbonate (134 g, 1.6 mol) and 4-(2-hydroxyeth-1-yl)piperidine acetic acid salt (38 g, 0.2 mol, from Step A) in 500 mL of 50% tetrahydrofuran in water. Added di-tert-butyl dicarbonate (35 g, 0.2 mol) and stirred at rt overnight. Diluted with ethyl acetate and extracted the aq. layer with 2xc3x97300 mL of ethyl acetate. Washed the combined organic layers with 2xc3x97300 mL of 1 N HCl and brine. Dried over magnesium sulfate and concentrated to afford 37.4 g (81%) of the title compound.
ESI-MS: 230 (M+H); HPLC A: 2.76 min.
Step C: 4-(2-Iodoeth-1-yl)-1-tert-butoxycarbonylpiperidine
Combined 4-(2-hydroxyeth-1-yl)-1-tert-butoxylcarbonylpiperidine (37.4 g, 0.16 mol, from Step B), triphenylphosphine (55 g, 0.21 mol) and imidazole (14 g, 0.21 mol) in 800 mL of 33% acetonitrile in ether. Cooled to 0xc2x0 C. and added iodine (56 g, 0.22 mol) portionwise. The iodine is de-colored until the endpoint of the reaction. Diluted with 1 L of ether. Washed organic layer with 2xc3x97500 mL each of sat""d. aq. Na2S2O3, sat. aq. CuSO4 and brine. Dried over magnesium sulfate, filtered and concentrated. Triphenylphosphine oxide precipitates. Added ether and filtered the slurry through a plug of silica gel. Purified a portion of the crude material by flash chromatography (5% ethyl acetate in hexane eluent) to afford the title compound.
1H-NMR (400 MHz, CDCl3): xcex44.10 (br s, 2 H), 3.23 (t, 2 H, J=7.2 Hz), 2.72 (br t, 2 H, 12.3 Hz), 1.79 (q, 2 H, J=7 Hz), 1.67 (br d, 2 H, 14 Hz), 1.61 (m, 1 H), 1.47 (s, 9 H), 1.14 (qd, 2 H, J=4.3, 12 Hz); ESI-MS: 340 (M+H); HPLC A: 3.74 min.
Step D: 4-(2-(4-Fluorophenylthio)eth-1-yl)-1-tert-butoxycarbonylpiperidine
To a slurry of sodium hydride (47 mg, 60% in mineral oil, 1.2 mmol) in tetrahydrofuran at 0xc2x0 C. was added 4-fluorothiophenol (0.1 mL, 0.94 mmol). The reaction mixture was warmed to rt. for 20 min, followed by addition of 4-(2-iodoeth-1-yl)-1-tert-butoxycarbonylpiperidine (265 mg, 0.78 mmol, from Step C). The reaction was then heated to reflux for 10 min, cooled and diluted with ether. The organic layer was washed with 1 N NaOH, dried over magnesium sulfate and concentrated to provide 252 mg (95%) of the title compound. ESI-MS: 340.0 (M+H); HPLC A: 4.07 min.
Step E: 4-(2-(4-Fluorophenylsulfonyl)eth-1-yl)piperidine trifluoroacetic acid salt
Added a solution of oxone (1.14 g, 1.86 mmol) in water to a solution of 4-(2-(4-fluorophenylthio)eth-1-yl)-1-tert-butoxycarbonylpiperidine (252 mg, 0.74 mmol, from Step D) in methanol at 0xc2x0 C. Warmed to rt. After 90 min., added an additional 0.5 g of oxone. After 3 h, the reaction mixture was diluted with methylene chloride and washed with 1 N NaOH containing sodium bisulfite. The aq. layer was extracted twice with methylene chloride, and the combined organic layers were dried over magnesium sulfate. The solution was concentrated and dissolved in 5% trifluoroacetic acid in methylene chloride for 1 h. The solvent was evaporated to afford 297 mg (100%) of the title compound. ESI-MS: 239.8 (M+H); HPLC A: 2.54 min.
Step A: N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-trifluoromethane sulfonate.
A dry flask under nitrogen was charged with a solution of sodium hexamethyldisilazide (11 mL, 1.0 M in THF) and was cooled to xe2x88x9278xc2x0 C. A solution of N-tert-butoxycarbonyl-4-piperidone (2.0 g, 10 mmol) in 10 mL THF was added dropwise via cannula. After 30 min. a solution of 2-(N,N-bis(trifluoromethanesulfonyl)amino-5-chloropyridine (4.7 g, 12 mmol) in 15 mL THF was added. The mixture was warmed to room temperature, quenched with sat""d ammonium chloride and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with sat""d brine then dried over sodium sulfate and concentrated. Flash chromatography (100 g silica, 10/1 Hexane/ethyl acetate) afforded 1.9 g (58%) of the title compound.
1H NMR (400 MHz, CDCl3). xcex41.5 (s, 9H), 2.4-2.48 (m, 2H), 3.62-3.68 (t, 2H), 4.05-4.07 (m, 2H), 5.77-5.8 (bs, 1H).
Step B: N-tert-Butoxycarbonyl-4-trimethylstannyl-1,2,5,6-tetrahydropyridine
A dry flask under nitrogen was charged with 20 mL THF, lithium chloride (1.6 g, 37.3 mmol), tetrakistriphenylphosphine palladium(0), (331 mg, 0.28 mmol) and hexamethyldistannane (1.2 mL, 5.7 mmol). N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-trifluoromethane sulfonate (1.9 g, 5.7 mmol) was added and the mixture was stirred overnight at 60xc2x0 C. The mixture was diluted with water and extracted with ethyl acetate (3xc3x97150 mL). The combined organic layers were dried over sodium sulfate and concentrated. Flash chromatography (100 g silica, 20/1 Hexane/ethyl acetate) afforded 1.56 g (79%) of the title compound.
1H NMR (300 MHz, CDCl3). xcex40.5 (s, 9H), 1.5 (s, 9H), 2.25-2.35 (m, 2H), 3.62-3.68 (t, 2H), 3.95-3.97 (m, 2H), 5.77-5.8 (bs, 1H).
Step C: 3-Bromo-5-benzylpyridine
A dry flask under nitrogen was charged with zinc chloride (16 mL, 0.5 M in THF, 8 mmol), and a solution of phenylmagnesium chloride (4 mL, 2.0 M in THF, 8 mmol). The mixture was heated to 50xc2x0 C. for 3h then cooled to room temperature and transferred via cannula to a solution of 3,5-dibromopyridine (1.26 g, 5.3 mmol), copper iodide (61 mg, 0.32 mmol), and bis(diphenylphosphino)ferrocene palladium dichloride (218 mg, 0.27 mmol) in 15 mL THF. The resulting mixture was heated to 50xc2x0 C. overnight. Sat""d ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated. Flash chromatography (8/1 hexanelethyl acetate) afforded 433 mg (33 %) of the title compound. 1H NMR (400 MHz, CDCl3), xcex44.02 (s, 2H), 7.18-7.4 (m, 8H), 7.65 (s, 1H).
Step D: 4-((5-Benzyl)pyrid-3-yl)piperidine di-TFA
A flask was purged with nitrogen and charged with DMF, 3-bromo-5-benzylpyridine (618 mg, 2.5 mmol, from Step C), tetrakis triphenylphosphine palladium (58 mg, 0.05 mmol), and N-tert-butoxycarbonyl-4-trimethylstannyl-1,2,5,6-tetrahydropyridine (1.04 g, 3 mmol). The mixture was heated to 100xc2x0 C. and stirred for 10 h. An additional portion of tetrakis triphenylphosphine palladium (40 mg, 0.03 mmol) was added and stirring was continued for 14 h. The solution was cooled and diluted with ethyl acetate then washed with water, dried over sodium sulfate and concentrated. Flash chromatography (2.5/1 hexane/ethyl acetate) afforded 590 mg (67%) of the coupling product. The product was dissolved in 4 mL methanol and 50 mg 10% Pd/C was added. The mixture was stirred under 1 atm of hydrogen for 3 h. The catalyst was filtered off and the residue was dissolved in 1/1 TFA/methylene chloride. Removal of the solvent and drying under vacuum afforded the title compound as its TFA salt.
1H NMR (500 MHz, CDCl3). xcex41.55-1.64 (m, 2H), 1.75-1.8 (d, 2H), 2.57-2.62 (m, 1H), 2.68-2.73 (t, 2H), 3.15-3.2 (d, 2H), 7.14-7.15 (d, 2H), 7.19-7.21 (m, 1H(, 7.26-7.32 (m, 3H), 8.30-8.31 (d, 2H).
Step A: 1-(t-Butoxycarbonyl)-4-cyanopiperidine
Isonipecotamide (10.0 g, 78.0 mmol) was added in portions to 25 mL of POCl3 at 0xc2x0 C. The cooling was removed and the mixture was allowed to reach rt. The mixture was heated at reflux for 2 h, then cooled to rt. The mixture was poured onto 100 g of ice. The pH of the aqueous mixture was adjusted to 11 with solid KOH and extracted with 4xc3x97200 mL of methylene chloride. The extracts were combined, dried over magnesium sulfate and concentrated to afford 8.0 g of crude (4-cyano)piperidine.
The crude (4-cyano)piperidine was dissolved in 50 mL of methanol and treated with 17.0 g (78.0 mmol) of di-t-butyl dicarbonate and the resulting mixture was stirred at rt for 1 h. The mixture was concentrated. Flash chromatography on 250 g of silica gel using 1:1 v/v hexanes/ether afforded 13.4 g (80%) of the title compound:
1H NMR (300 MHz) xcex41.46 (s, 9H), 1.76-1.96 (4H), 2.78-2.82 (m, 1H), 3.3xe2x80x943.37 (m, 2H), 3.63-3.69 (m, 2H).
Step B: 1-(t-Butoxycarbonyl)4-(1H-tetrazol-5-yl)piperidine
A mixture of 2.10 g (10.0 mmol) of 1-(t-butoxycarbonyl)-4-cyanopiperidine (from Step A), 1.95 g (30.0 mmol) of sodium azide and 1.60 g (30.0 mmol) of ammonium chloride in 20 mL of DMF was stirred at 100xc2x0 C. for 20 h. The mixture was cooled and partitioned between 200 mL of methylene chloride and 200 mL of 1.0 N HCl and the layers were separated. The organic layer was washed with 200 mL of water, dried over magnesium sulfate and concentrated. Flash chromatography on 50 g of silica gel using 4:1 v/v methylene chloride/ethyl acetate+1% acetic acid, then 2:1 v/v methylene chloride/ethyl acetate+1% acetic acid as the eluent afforded 1.51 g (60%) of the title compound:
1H NMR (500 MHz) xcex41.49 (s, 9H), 1.83-1.89 (m, 2H), 2.13-2.15 (m, 2H), 2.96-3.04 (m, 2H), 3.13-3.36 (m, 1H), 4.14-4.22 (m, 2H).
Step C: 1-(t-Butoxycarbonyl)-4-((1-benzyl)-(1H)-tetrazol-5-yl)piperidine and 1-(t-Butoxycarbonyl)-4-((2-benzyl)-(2H)-tetrazol-5-yl)piperidine
A solution of 438 mg (1.7 mmol) of 1-(t-butoxycarbonyl)4-(1H-tetrazol-5-yl)piperidine (from Step B) in 2 mL of DMF at 0xc2x0 C. was treated with 83 mg (0.50 mmol) of sodium hydride (60% in mineral oil) and 0.41 mL (3.4 mmol) of benzyl bromide. The resulting mixture was warmed to rt and stirred for 2.5 h. The mixture was partitioned between 50 mL of ether and 50 mL of water and the layers were separated. The organic layer was washed with 50 mL sat""d brine, dried over magnesium sulfate and concentrated. Flash chromatography using 2:1 v/v methylene chloride/ether, then 1:2 v/v methylene chloride/ether afforded 85 mg (15%) of 1-(t-butoxycarbonyl)-4-(2-(benzyl)-(2H)tetrazol-5-yl)piperidine. Elution with 2:1 v/v ethyl acetate/methylene chloride afforded 95 mg (17%) of 1-(t-butoxycarbonyl)-4-(1-(benzyl)-(1H)-tetrazol-5-yl)piperidine.
For 1-(t-butoxycarbonyl)4-(2-(benzyl)-(2H)-tetrazol-5-yl)piperidine: 1H NMR (500 MHz) xcex41.47 (s, 9H), 1.76-1.84 (2H), 2.02-2.05 (2H), 2.91-2.95 (2H), 3.07-3.12 (m, 1H), 4.00-4.20 (2H), 5.71 (s, 2H), 7.35-7.40 (5H). For 1-(t-butoxycarbonyl)-4-(1-(benzyl)-(1H)-tetrazol-5-yl)piperidine: 1H NMR (500 MHz) xcex41.45 (s, 9H), 1.59-1.61 (2H), 1.76-1.84 (2H), 2.70-2.80 (2H), 2.85-2.89 (m, 1H), 4.004.20 (2H), 5.55 (s, 2H), 7.17-7.19 (2H), 7.36-7.39 (3H).
Step D: 4-(2-(Benzyl)-(2H)-tetrazol-5-yl)piperidine
A solution of 85 mg (0.25 mmol) of 1-(t-butoxycarbonyl)4-((2-benzyl)tetrazol-5-yl)piperidine (from Step C) in 2 mL of 1:1 v/v methylene chloride/TFA was stirred at rt for 2 h. The solution was concentrated. Flash chromatography on silica gel using 19:1:0.1 v/v/v methylene chloride/methanol/NH4OH as the Eluant afforded 57 mg (94%) of the title compound.
Step A: N-tert-Butoxycarbonyl-4-piperid-4-ylacetaldehyde
A solution of oxalyl chloride (2.4 mL, 27.5 mmol) in 125 mL methylene chloride was cooled to xe2x88x9278xc2x0 C. and DMSO (3.3 mL, 47.1 mmol) was added slowly. After 10 min a solution of 2-(N-tert-butoxycarbonylpiperidin-4-yl)ethanol (4.5 g, 19.6 mmol) in 10 mL methylene chloride was added. The mixture was stirred for 20 min then triethylamine (13.6 mL, 98.1 mmol) was added and the mixture was warmed to room temperature. After 30 min the mixture was diluted with ethyl acetate and washed with water (3xc3x97). The organic portion was dried over sodium sulfate and concentrated. Flash chromatography (3/1 hexane/ethyl acetate) afforded 3.7 g (83%) of the desired aldehyde.
1H NMR (400 MHz, CDCl3). xcex41.13-1.43 (m, 2H), 1.48 (s, 9H), 1.68-1.77 (m, 2H), 2.04-2.11 (m, 1H), 2.38-2.41 (d, 2H), 2.71-2.8 (m, 2H), 4.04-4.14 (m, 2H), 9.8 (s, 1H).
Step B: 3-Ethyl-4-(N-t-butoxycarbonylpiperidin-4-yl)-(1H)-pyrazole
A solution of N-tert-butoxycarbonylpiperidin-4-ylacetaldehyde (4.5 g, 19.8 mmol, from Step A), and morpholine (1.7 mL, 19.8 mmol) in 100 mL benzene was refluxed using a dean-stark apparatus. After refluxing over night the mixture was concentrated to provide the enamine. The crude enamine was dissolved in 40 mL methylene chloride and the solution was cooled to 10xc2x0 C. Propionyl chloride (1.7 mL, 19.8 mmol) and then triethylamine (1.4 mL, 9.9 mmol) were added. The mixture was gradually warmed to room temperature and stirred for 40 h then concentrated. The residue was dissolved in 60 mL of ethanol and hydrazine (6.2 mL, 198 mmol) was added. The solution was refluxed for 5 h. The solvent was removed and ethyl acetate was added. The organic was washed with water and sat""d sodium chloride then dried over magnesium sulfate and concentrated. Flash chromatography (0.5% methanol/methylene chloride- greater than 2% methanol/methylene chloride) afforded 2.1 g (38 %) of the title compound.
1H NMR (400 MHz, CDCl3). xcex41.25-1.31 (t, 3H), 1.44-1.57 (m, 1H), 1.46 (s, 9H), 1.78-1.83 (s, 2H), 2.53-2.6 (m, 1H), 2.62-2.7 (q, 2H), 2.77-2.82 (m, 2H), 4.12-3.23 (m, 2H), 7.32 (s, 1H).
Step C: 4-(1-(4-Methylsulfonylbenzyl)-3-ethyl-(1H)-pyrazol-4-yl)-N-t-butoxylcarbonylpiperidine
A dry flask was charged with 5 mL DMF and sodium hydride (224 mg, 60% dispersion in mineral oil, 5.6 mmol). A solution of 3-ethyl-4-(N-t-butoxycarbonylpiperidin-4-yl)-(1H)-pyrazole (1.3 g, 4.7 mmol, from Step B) in 5 mL DMF was added. The mixture was stirred for 1 h at room temperature and a solution of (4-methylsulfonyl)benzyl chloride (1.05 g, 5.2 mmol) in 5 mL DMF was added. After 3 h the solvent was removed and the product was purified by preparative HLC (35% acetonitrile/water - greater than 85% acetonitrile/water, C-18 stationary phase) to give 0.5 g of product as a mixture of isomeric N-alkylation products. The isomers were separated by preparative HPLC using a chiral stationary phase (Chiracel-OJ, 1/1 hexane/ethanol) to provide 210 mg (10%) of the desired isomer along with 70 mg (3%) of the undesired isomer. The substitution pattern of both isomers was determined by NOE difference.
1H NMR (400 MHz, CDCl3, desired isomer). xcex41.25-1.31 (t, 3H), 1.38-1.47 (m, 1H) 1.46 (s, 9H), 1.8-1.85 (m, 2H), 2.5-2.6 (m, 1H), 2.6-2.66 (q, 2H), 2.75-2.82 (m, 2H), 3.03 (s, 3H), 4.13-4.22 (m, 2H), 5.32 (s, 2H), 7.13 (s, 1H), 7.28-7.31 (d, 2H), 7.89-7.91 (d, 2H).
Step D: 4-(1-(4-Methylsulfonylbenzyl)-3-ethyl-(1H)-pyrazol-4-yl)piperidine di-TFA salt
4-((1-(4-Methylsulfonylbenzyl)-3-ethyl)-(1H)-pyrazol-4-yl)-N-t-butoxylcarbonylpiperidine from Step C was treated with TFA for 1 h and evaporated to afford the title compound as the TFA salt.
Step A: 1-t-Butyloxycarbonyl-4-(nitromethylcarbonyl)piperidine
To a solution of 1-t-butyloxycarbonylpiperidine-4-carboxylic acid (22.9 g, 100 mmol) in 200 mL of anhydrous THF was added carbonyl diimidazole (20.0 g, 125 mmol) under nitrogen. Effervescence was observed and the reaction mixture was stirred 1 h at ambient temperature. Freshly distilled nitromethane (7.4 mL, 135 mmol) followed by DBU (21.0 mL, 140 mmol) were added. The resulting reaction mixture was stirred for 1 day at room temperature. After dilution with ethyl acetate, the mixture was washed with 2N HCl and brine. The organic phase was dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by the purification of the residue on silica gel using 1:1 mixture of ethyl acetate -hexane with 1% acetic acid as an eluent gave 25 g of the nitroketone as a semi solid. After removal of last traces of acetic acid by azeotroping with toluene.
1H NMR (CDCl3) 1.48 (9H,s); 1.65, 1.90, 2.65, 2.80, 4.15 (all multiplets); 5.36 (2H,s).
Step B: 1-t-Butyloxycarbonyl-4-(1-hydroxy-2-nitro)ethyl)piperidine
Sodium borohydride (1.52 g, 40 mmol) was added portionwise to a suspension of 1-t-butyloxycarbonyl-4-(nitromethylcarbonyl) piperidine (10.5 g, 40 mmol) from Step A in methanol (80 mL) at 0xc2x0 C. After 6.5 h, the solvent was removed in vacuo. The residue was diluted with ethyl acetate and stirred with 2N HCl and the layers were separated. The organic phase was washed with brine and dried over magnesium sulfate. Solvent removal gave 9.1 g of the desired product as amorphous solid.
1H NMR(CDCl3) 1.45 (9H,s); 4.45 (2H, m); 1.3, 1.65, 1.85, 2.7, 4.2 (multiplets)
Step C: 1-t-Butyloxycarbonyl-4-(1-hydroxy-2-amino)ethylpiperidine
To a stirred suspension of 1-t-butyloxycarbonyl-4-(1-hydroxy-2-nitro)ethyl)piperidine (9.0 g, 33 mmol) from Step B in anhydrous methanol (100 mL), 10% Pdxe2x80x94C (2.0 g) followed by ammonium formate (12.6 g, 200 mmol) were cautiously added. The reaction mixture was stirred 1.5 days at ambient temperature. The catalyst was filtered through a pad of celite and washed with methanol. The filtrate was concentrated after adding 42 mL of triethylamine to free the product from any formic acid salts. The residue was purified on silica gel using 10:10:1 mixture of ethyl acetate, hexane and NH4OH as solvent to yield 6.9 g of the desired amino alcohol as white solid after azeotroping with toluene.
1H NMR (CDCl3): 1.5 (9H,s); 3.6 (2H,s) 1.2, 1.75, 2.6, 3.24, 3.4, 4.15 (all multiplets).
Step D: 1-t-Butyloxycarbonyl-4-(1-hydroxy-2-phenylacetylamino)ethylpiperidine
Phenylacetyl chloride (0.44 mL, 3.3 mmol) was added dropwise to a mixture of 1-t-butyloxycarbonyl-4-(1-hydroxy-2-amino)ethylpiperidine (0.732 g, 3 mmol) from Step C and triethylamine (0,465 mL, 3.3 mmol) in methylene chloride (15 mL) at ice bath temperature and the bath was removed. After stirring for 3 h at room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous magnesium sulfate. Solvent removal gave a crude product which was used in the next step without further purification.
1H NMR (CDCl3) 1.45 (9H,s); 3.42 (2H,s); 1.2, 1.75, 2.6, 3.2, 3.42, 4.12 (all multiplets).
Step E: 1-t-Butyloxycarbonyl-4-(2-phenylacetamido)acetylpiperidine
To a stirred solution of 1-t-butyloxycarbonyl-4-(1-hydroxy-2-phenylacetylamino)ethylpiperidine from Step D in acetone at ice bath temperature 8 N Jones reagent was added until the orange color of the reagent persisted. After stirring for 0.5 h, 0.2 mL of isopropanol was added and the stirring was continued for 0.5 h. Solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. Solvent removal gave an oil which was purified on silica gel using 1: ethyl acetate-hexane as solvent to yield 606 mg of the desired ketone as oil.
1H NMR (CDCl3): 1.46 (9H,s); 3.62 (2H,s); 4.18 (2H, d, J=2); 1.45, 1.8, 2.5, 4.1, 7.35, 7.4 (all multiplets)
Step F: 1-t-Butyloxycarbonyl-4-(2-benzylthiazol-5-yl)piperidine
A mixture of 1-t-butyloxycarbonyl-4-(2-phenylacetamido)acetylpiperidine (595 mg, 1.653 mmol) from Step E and Lawesson""s reagent (607 mg, 1.66 mmol) in 5 mL of toluene was heated to 120xc2x0 C. for 3.5 h. After cooling, 3:1 mixture of ethyl acetate and methylene chloride and saturated sodium bicarbonate solution were added and the mixture was stirred for 0.5 h. The organic phase was separated and washed with brine. Solvent removal gave a crude product which was purified on silica gel using 2:3 mixture of ethyl acetate-hexane as solvent to give 330 mg of the desired product.
1H NMR (CDCl3): 1.45 (9H,s); 4.4 (2H,s); 7.46 (1H,s); 1.58, 1.95, 2.85, 2.95, 4.2 multiplets).
Step G: 4-(2-Benzylthiazol-5-yl)piperidine di-hydrochloride
Acetyl chloride (0.3 mL) was added dropwise to a solution 1-t-butyloxycarbonyl-4-(2-benzylthiazol-5-yl)piperidine from Step F in methanol (2 mL) at ice bath temperature. The reaction mixture was stirred 3.5 h as it warmed to room temperature. Solvent removal in vacuo gave the desire amine as glassy solid.
1H NMR (CD3OD): 4.58 (2H,s); 8.02 (1H,s); 1.94, 2.24, 3.15, 3.35, 3.45 (all multiplets)
Step A: 1-t-Butyloxycarbonyl-4-(2-hydroxyethyl)piperidine
A mixture of 4-(2-hydroxyethyl) piperidine (5.0 g, 40 mmol), di-t-butyl dicarbonate (10.9 g, 50 mmol), and triethylamine (7 mL, 50 mmol) in 100 mL of anhydrous methylene chloride was stirred overnight at room temperature. Volatiles were removed in vacuo and the resulting oil was purified on a silica gel column using 20% ethyl acetate in hexane as eluent to give 7.9 g of the desired product as a colorless oil.
Step B: 1-t-Butyloxycarbonyl-4-formylylmethylpiperidine
Oxalyl chloride (2.2 mL, 25 mmol) was added to 75 mL of anhydrous methylene chloride at xe2x88x9278xc2x0 C. DMSO (3.5 mL, 50 mmol) was then added dropwise over 5 min, and the resulting mixture was stirred for 15 min. 1-t-Butyloxycarbonyl-4-(2-hydroxyethyl)piperidine (2.29 g, 10 mmol, Step A) was dissolved in 5 mL of anhydrous methylene chloride and added over 10 min to the above mixture. After stirring 30 min, DIEA (17.4 mL, 100 mmol) was added over 10 min. The mixture was then warmed to 0xc2x0 C. and maintained at that temperature for 1 h. After quenching with water, the reaction mixture was diluted with 75 mL of methylene chloride and the layers were separated. The organic phase was washed with 3xc3x9750 mL of water and dried over anhydrous magnesium sulfate. Solvent removal gave an oil, which was purified on silica gel using 20% ethyl acetate in hexane to give 2.05 g of the desired aldehyde which hardened overnight into an oily solid.
NMR: xcex42.15 (2H, d, J=3); 9.8 (1H,s); 1.2, 1.5, 1.7, 2.75, 4.1 (all multiplets)
Step C: 1-t-Butyloxycarbonyl4-(xcex1-bromo-formylmethyl)piperidine
A mixture of 1-t-butyloxycarbonyl-4-formylylmethylpiperidine (0.57 g, 2.25 mmol, step B), 3,3-dibromo-Meldrum""s acid (0.75 g, 2.5 mmol) in 10 mL of anhydrous ether was stirred for 2 days at room temperature under nitrogen. The reaction mixture was diluted with ethyl acetate and washed with sat""d. sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate. Solvent removal and purification on silica gel using 20% ethyl acetate in hexane as solvent gave 59% of the pure bromo aldehyde as a colorless oil.
1H NMR: xcex4(CDCl3): 4.04 (1H,dd; J=1.5; 2); 9.46 (1H,d; J=1.5) 1.35, 1.7, 1.95, 2.1, 2.75, 4.2 (all multiplets)
Step D: 1-t-Butyloxycarbonyl-4-(2-benzylthiazol-5-yl)piperidine
A mixture of 1-t-butyloxycarbonyl-4-(xcex1-bromo-formylmethyl)piperidine (612 mg, 2 mmol), benzyl thioamide (500 mg, 2.55 mmol) in 10 mL of anhydrous toluene was heated to reflux for 6 h. Solvent was then removed and the residue was purified on silica gel using 25% ethyl acetate in hexane as solvent to give 350 mg of the desired thiazole as an oil.
1H NMR (CDCl3): 1.45 (9H,s); 4.4 (2H,s); 7.46 (1H,s); 1.58, 1.95, 2.85, 2.95, 4.2 multiplets).
Step E: 4-(2-Benzylthiazol-5-yl)piperidine di-hydrochloride
The title compound was prepared by removal of the protecting group of 1-t-butyloxycarbonyl-4-(2-benzylthiazol-5-yl)piperidine as described in Example 22, Step G.
The title thiazole was prepared according to the method of Procedure 22 by substituting nitroethane for nitromethane in Step A.
The title compound was obtained by the procedure of Procedure 22 by substituting nitropropane for nitromethane in Step A.
Step A: 1-t-Butyloxycarbonyl-4-((1-hydroxy)-2-(2-pyridylmethyl)carbonylamino)ethylpiperidine
To 0.361 g (2.08 mmol) of 2-pyridyleacetic acid hydrochloride in 8 mL of methylene chloride, 0.337 g (2.5 mmol) of 1-hydroxybenzotriazole, 0.478 g (2.5 mmol) of EDC and 0.57 mL (5.2 mmol) of N-methylmorpholine were added. After 10 min 0.508 g (2.08 mmol) of 1-t-butyloxycarbonyl-4-(2-amino-1-hydroxy)ethylpiperidine from Procedure 22, Step C was added and the solution was stirred overnight. The reaction was quenched with saturated sodium bicarbonate and extracted with methylene chloride. The combined methylene chloride layer was washed with brine, dried and concentrated. The residue was chromatographed on a flash column using a gradient of 5-10% methanol in ethyl acetate containing 1% triethylamine to isolate 0.68 g of the desired product.
1H NMR (CDCl3): xcex41.24 (m, 3H), 1.45 (s, 9H), 1.58 (m, 1H), 1.82 (m, 1H), 2.6 (br, 2H), 3.21 (m, 1H), 3.49 (m, 2H), 3.75 (s, 2H), 4.12 (br, 2H), 7.22 (m, 1H), 7.29 (d, 1H), 7.69 (m, 1H), 852 (m, 1H).
Step B: 1-t-Butyloxycarbonyl-4-(2-(2-pyridylmethyl)carbonylamino)acetylpiperidine
To a solution of 0.22 nL (3.2 mmol) of DMSO in 1 mL of methylene chloride cooled in a dry ice-acetone bath, 0.14 mL (1.6 mmol) of oxalyl chloride was added. After 0.5 h, 0.145 g of 1-t-butyloxycarbonyl-4-((1-hydroxy)-2-(2-pyridylmethyl)carbonylamino)ethylpiperidine (Step A) in 1 mL of methylene chloride was added. After 1 h, 0.89 mL (6.38 mmol) of triethylamine was added, the cold bath was removed and the reaction was stirred for 1.5 h. The solution was partitioned between water and methylene chloride. The organic layer was washed with brine, dried and concentrated. The residue was purified on a prep TLC plate using 5% methanol-ethyl acetate as an eluent to furnish 67 mg of the desired product.
1H NMR (CDCl3): xcex41.45 (s, 9H),1.5-2.0 (m, 4H), 2.53 9m, 1H), 2.77 (br, 2H), 3.79 (s, 2H), 4.1 (br, 2H), 4.22 (d, 2H), 7.2-8.0 (m, 3H), 8.61 (d, 1H).
Step C: 1-t-Butyloxycarbonyl-4-(2-(2-pyridylmethyl)thiazol-5-yl)piperidine
The title compound was prepared by reacting 1-t-butyloxycarbonyl-4-(2-(2-pyridylmethyl)carbonylamino)acetylpiperidine (Step B) with Lawesson""s reagent as described in Procedure 22, Step F.
1H NMR (CDCl3): xcex41.47 (s, 9H), 1.6 (m, 2H), 1.99 (m, 2H), 2.82 (br, 2H), 2.94 (m, 1H), 4.17 (br, 2H), 4.48 (s, 2H), 7.2-7.8 (m, 4H), 8.6 (br, 1H).
Step D: 4-(2-(2-Pyridylmethyl)thiazole-5-yl)piperidine di-HCl salt
Removal of the t-butyloxycarbonyl protecting group as described in Procedure 22, Step G furnished the title compound.
Step A: 1-(t-Butoxycarbonyl)-4-(imidazo[1,2-a]pyridin-3-yl)piperidine
To a solution of 1.15 g of 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)piperidine (from Procedure 23, Step C) in 15 mL ethanol was added 388 mg of 2-aminopyridine. After refluxing for 18 h, the solvent was evaporated. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. Aqueous layer was extracted with ethyl acetate (3xc3x97). The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography with 50% ethyl acetate in hexanes, followed by 100% ethyl acetate to give 401 mg of the title compound as a solid.
1H NMR (500 MHz, CDCl3) xcex41.48 (s, 9H), 1.70 (m, 2H), 2.06 (d, J=13 Hz, 2H), 2.93-3.02 (m, 3H), 4.26 (br, 2H), 6.87 (t, J=6.8 Hz, 1H). 7.21(m, 1H), 7.44 (s, 1H), 7.69(d, J=9.2 Hz, 1H), 7.99 (d, J=6.9 Hz, 1H).
Step B: 4-Imidazo[1,2-a]pyridin-3-yl)piperidine di-TFA salt
To 100 mg of 1-(t-butoxycarbonyl)-4-(imidazo[1,2-a]pyridin-3-yl)piperidine from Step A was added 2 mL TFA. The reaction was stirred at rt for 1 h. The mixture was concentrated under reduced pressure to afford 180 mg of a viscous oil.
Step A: 2-Amino-4-t-butylpyridine
To 790 mg of sodium amide were added 20 mL of N,N-dimethylaniline and 2.74 g of 4-t-butyl pyridine at rt. The mixture was stirred at 150xc2x0 C. for 6 h. During this period, 3 more portions of sodium amide (790 mg each) were added. The reaction was cooled down to rt. The mixture was partitioned between ethyl acetate and water. Aqueous layer was extracted with ethyl acetate (3xc3x97). The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography with 50% ethyl acetate in hexanes followed by 100% ethyl acetate to give 1.68 g of the title compound as a solid:
1H NMR (500 MHz, CDCl3) xcex41.21 (s, 9H), 6.44 (t, 1H), 6.6.62 (dd, J=5.5 Hz and, 1H), 7.94 (d, J=5.5 Hz, 1H).
Step B: 1-(t-Butoxycarbonyl)-4-(7-t-butylimidazo[1,2-a]pyridin-3-yl)piperidine
The title compound was prepared from 470 mg of 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)piperidine (from Procedure 23, Step C) and 277 mg of 2-amino-4-t-butyl pyridine (from Step A) in 12 mL ethanol using a procedure analogous to that described in Example 235 , Step A to provide 130 mg of the title compound as a solid.
Step C: 4-(7-t-Butylimidazo[1,2-a]pyridin-3-yl)piperidine, TFA salt
The title compound was prepared from 35 mg of 1-(t-butoxycarbonyl)-4-((7-t-butyl)imidazo[1,2-a]pyridin-3-yl)piperidine (from Step B) in 2 mL of TFA, using a procedure analogous to that described in Procedure 27, Step B to provide 60 mg of the title compound as a viscous oil.
Step A: 2-Ethyl-imidazo[1,2-a]pyridine
The title compound was prepared from 2-aminopyridine and 1-bromo-2-butanone, employing procedures analogous to those described in Procedure 27 Step A.
1H NMR (500 MHz, CDCl3): xcex41.34 (t, J=7.3 Hz, 3H), 2.82 (q, J=7.6 Hz, 2H), 6.70 (t, J=6.6 Hz, 1H), 7.10 (m, 1H), 7.32 (s, 3H), 7.51 (d, J=8.9 Hz, 1H), 8.03 (dd, J=6.6, 0.9 Hz, 1H).
Step B: 3-Bromo-2-ethyl-imidazo[1,2-a]pyridine
To a solution of 2-ethyl-imidazo[1,2-a]pyridine (2.17 g, 14.9 mmol) in ethanol (25 mL) was added bromine (2.0 g, 12.5 mmol) in water (5 mL) dropwise at rt. After stirring at rt for 4h, ethanol was evaporated under reduced pressure. The residue was basified with aqueous sodium bicarbonate and extracted with methylene chloride (3xc3x97). The organic phase was washed with brine and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography eluting with 20 % ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes afforded the title compound (1.88 g) as a viscous oil.
1H NMR (500 MHz, CDCl3): xcex41.36 (t, J=7.5 Hz, 3H), 2.83 (q, J=7.6 Hz, 2H), 6.88 (t, J=6.8 Hz, 1H), 7.20 (m, 1H), 7.55 (dd, J=8.9, 0.9 Hz, 1H), 8.05 (dd, J=6.9, 1.2 Hz, 1H).
Step C: 2-Ethyl-3-(4-pyridyl)-imidazo[1,2-a]pyridine
To a solution of 3-bromo-2-ethyl-imidazo[1,2-a]pyridine (1.4 g, 6.28 mmol), 4-tributylstannylpyridine (2.31 g, 6.28 mmol) and Pd (II) (Ph3P)2Cl2 (442 mg, 0.63 mmol) in toluene (5 mL) was added lithium chloride (26.7 mg, 0.63). After refluxing for 18 h, the mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3xc3x97). Combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography eluting with 100% ethyl acetate, then 10% methanol in methylene chloride afforded the title compound (543 mg) as a viscous oil.
1H NMR (500 MHz, CDCl3): xcex41.36 (t, J=7.5 Hz, 3H), 2.84 (q, J=7.5 Hz, 2H), 6.68 (dt, J=6.8, 1.1 Hz, 1H), 7.21 (m, 1H), 7.39 (dd, J=5.9, 1.6 Hz, 2H), 7.61 (dd, J=8.9, 1.0 Hz, 1H), 8.75 (d, J=5.9 Hz, 2H).
Step D: 4-(2-Ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)piperidine, acetic acid salt
A solution of 2-ethyl-3-(4-pyridyl)-imidazo[1,2-a]pyridine (700 mg, 3.13 mmol) in ethanol (12 mL) and acetic acid (4 mL) was hydrogenated using Platinum (IV) oxide (40 mg) under 40 psi of H2 gas in a Parr shaker at rt for 18 h. The mixture was filtered through celite and concentrated to give the title compound (1.47 g) as a viscous oil.
Step A: 1-Benzoylisonipecotic Acid
To a solution of 10 g of isonipecotic acid in 100 mL of water was added 31 mL of 5 N NaOH at 0xc2x0 C. The reaction was warmed to room temperature and stirred for 0.5 h. The reaction was again cooled to 0xc2x0 C. and 11.97 g of benzoyl chloride was added. The reaction was then warmed to room temperature and stirred for 1.5 h. Concentrated HCl was then added until a precipitate formed. The mixture was extracted with 3xc3x97150 mL of ethyl acetate and the combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride. Ether was then slowly added to precipitate the product which was filtered to give 8 g of the title compound.
1H NMR (500 MHz) 1.83 (m, 3H), 2.10 (m, 1H), 2.65 (m, 1H), 3.12 (m, 2H), 3.79 (m, 1H), 4.53 (m, 1H), 7.38 (m, 5H).
Step B: 4-hydroxymethyl-1-benzoylpiperidine
To a solution of 2 g of 1-benzoylisonipecotic acid (Step A) in 50 mL THF at 0xc2x0 C. were added 1.47 g of triethylamine and 1.99 g of isobutyl chloroformate. The reaction was stirred for 1 h at 0xc2x0 C. To a solution of 1.10 g of sodium borohydride in 30 mL DMF at 0xc2x0 C. was slowly added the above THF mixture. The reaction was again stirred for 1 h at 0xc2x0 C. Water (80 mL) was slowly added to the reaction and the mixture was extracted 5xc3x9780 mL ethyl acetate and the combined organic layers were dried over magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 1:1 hexane:ethyl acetate followed by hexane: ethyl acetate: methanol, 50:50:5 to give 1.865 g of the title compound.
ESI-MS 219.9 (M+H); HPLC A: 2.34 min. (65148-258)
Step C: 1-Benzoylpiperidine-4-carboxaldehyde
To 1.99 g of dimethyl sulfoxide in 45 mL methylene chloride at xe2x88x9278xc2x0 C. was added 2.16 g of oxalyl chloride. After 10 min, 1865 g of 4-hydroxymethyl-N-benzoylpiperidine (Step B) in 15 mL of methylene chloride was added at xe2x88x9278xc2x0 C. and stirred for 30 min. DIEA (5.49 mL) was added and this mixture was stirred for an additional 30 min. at xe2x88x9278xc2x0 C. and then warmed to room temperature and stirred another 30 min. The reaction was quenched with 50 mL water and extracted with 3xc3x9750 mL methylene chloride. The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed with 2:1 hexane:ethyl acetate followed by 1:1 hexane:ethyl acetate to give 1.445 g of the title compound.
1H NMR (500 MHz) 1.72 (m, 2H), 1.90 (m, 1H), 2.14 (m, 1H), 2.58 (m, 1H), 3.21 (m, 2H), 3.68 (m, 1H), 4.41 (m, 1H), 7.39 (m, 5H), 9.72 (m, 1H).
Step D: 4-(1-hydroxy-prop-2-enyl)-1-benzoyl piperidine
To a solution of 500 mg of 1-benzoylpiperidine-4-carboxaldehyde (Step C) in 10 mL THF at xe2x88x9278xc2x0 C., was added 2.99 mmol of vinyl magnesium bromide. The solution was warmed to 0xc2x0 C. and stirred for 1 h. The reaction was quenched with 15 mL of aq. ammonium chloride and extracted with 3xc3x9720 mL ether and the combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography with 2:1 hexane:ethyl acetate followed by 1:1 hexane:ethyl acetate followed by hexane: ethyl acetate:methanol, 50:50:5 to give 411 mg of the title compound.
1H NMR (500 MHz) 1.31 (m, 2H), 1.74 (m, 5H), 2.69 (m, 1H), 2.92 (m, 1H), 4.80 (m, 1H), 3.68 (m, 1H), 5.22 (dd, 2H), 5.84 (m, 1H), 7.43 (m, 5H).
Step E: 4-(1-Phenylacetyoxy-prop-2-enyl)-1-benzoylpiperidine
To 264 mg of 4-(1-hydroxy-prop-2-enyl)-1-benzoylpiperidine (Step D) in 5 mL DMF was added 220 mg of phenyl acetic acid, 292 mg of 1-hydroxybenzotriazole, 414 mg of EDC, and 419 mg of DIEA. The reaction was stirred at room temperature overnight. The solution was diluted with 50 mL of ether and washed with 2xc3x9740 mL water. The aqueous layers were then extracted with 2xc3x9750 mL ether and the combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography with 4:1 hexane:ethyl acetate followed by 2:1 hexane:ethyl acetate to give 123 mg of the title compound.
ESI-MS 364.1 (M+H).
Step F: 1-Benzoyl-4-(2-benzyloxazol-5-yl)piperidine
Ozone was bubbled through a solution of 120 mg of 4-(1-phenylacetyoxy-prop-2-enyl)-1-benzoylpiperidine (Step E) in 8 mL methylene chloride at xe2x88x9278xc2x0 C. until the reaction turned blue. To this solution 205 mg of methyl sulfide was added and the reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give 121 mg of the residue. This residue was dissolved in 3 mL of acetic acid and 76 mg of ammonium acetate was added. The reaction was stirred at 110xc2x0 C. for 2.5 h, 20 mL of water was added and the mixture was extracted with 3xc3x9720 mL methylene chloride. The combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography with 2:1 hexane:ethyl acetate followed by 1:1 hexane:ethyl acetate followed by hexane:ethyl acetate:methanol, 50:50:5 to give 40 mg of the title compound.
ESI-MS 347.0 (M+H); HPLC A: 3.68 min.
Step G: 4-(2-Benzyloxazol-5-yl)piperidine
To 40 mg of 1-benzoyl-4-(2-benzyloxazol-5-yl)piperidine (step F) in 4.5 mL methanol and 0.5 mL water was added 260 mg of potassium hydroxide. The reaction was stirred at 80xc2x0 C. overnight, 20 mL of water was added and the mixture was extracted with 3xc3x9720 mL ethyl acetate. The combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 22 mg of the title compound.
ESI-MS 242.9 (M+H); HPLC A: 2.29 min.
Step A: 4-Bromoacetyl-1-(t-butoxycarbonyl)piperidine
To a freshly prepared solution of LDA (from diisopropylamine (0.61 g, 6.0 mmol) and n-butyl lithium (2.2 mL, 2.5 M sol""n. In hexane) in 10 mL THF at xe2x88x9278xc2x0 C. was added a solution of 4-acetyl-1-(t-butoxycarbonyl) piperidine (1.0 g, 4.7 mmol) in 2.0 mL THF and the resultant mixture was stirred for 20 min. A mixture of trimethylsilyl chloride and triethylamine (1.37 mL, 10.8 mmol and 2.16 mL, 15.5 mmol) was added and the reaction mixture was gradually warmed to rt and stirred for an additional 1 h. All the volatile were removed and the crude silyl enol ether was dissolved in 10 mL of THF and the mixture was cooled to 0xc2x0 C. To this mixture was added in succession propylene oxide (1.0 mL) and NBS (1.0 g) and the mixture was stirred for 15 min, quenched with a saturated sodium bicarbonate followed by extraction with methylene chloride. The methylene chloride layer was washed with brine, dried, evaporated and purified by silica column chromatography. Elution with methylene chloride and ether (19:1) gave the title compound (1.11 g) as a yellow solid.
1HNMR (500 MHz, CDCl3): xcex44.16 (s, 2H), 4.12 (m, 2H), 2.79-2.84 (m, 3H), 1.47 (s, 3H).
Step B: 4-(2-(2,6-Dichlorobenzyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine
A mixture of the bromo compound (0.4 g, 1.36 mmol) from Step A and 2,6-dichlorophenylacetamidine (0.55 g, 2.7 mmol) in 30 mL of chloroform was refluxed for 4 h. The reaction mixture was filtered. The filtrate was evaporated and purified by silica column chromatography. Elution with hexane:ethyl acetate:methanol 49:49:2 gave (0.28 g) of the title compound.
1HNMR (500 MHz, CDCl3): xcex47.35-7.15 (m, 3H), 6.55 (s, 1H), 4.45 (s, 2H), 4.14 (br, 2H), 2.81-2.69 (m, 3H), 1.46 (s, 3H).
Step C: 4-((2-Benzyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine
A mixture of 4-(2-(2,6-dichlorobenzyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine (0.51 g, 1.24 mmol) from Step B, Pd/C (0.13 g) and ammonium formate (1.5 g, 24.8 mmol) in 8 mL of methanol was refluxed for 30 min. The reaction mixture was filtered and the filtrate was evaporated. The residue was partitioned between methylene chloride and water (200 mL). The methylene chloride layer was washed with brine, dried, evaporated and purified by silica column chromatography. Elution with 3% methanol-methylene chloride gave (0.35 g) of the title compound.
1HNMR (500 MHz, CDCl3): xcex47.34-7.22 (m, 5H), 6.58 (s, 1H), 4.18 (br, 2H), 4.08 (s, 2H), 2.71 (br, 2H), 2.68 (m, 1H), 1.47 (s, 3H).
Step D: 4-(2-Benzyl-1,3-imidazol-5-yl)piperidine hydrochloride
To 4-((2-benzyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl) piperidine (0.16 g) from Step C in 2 mL of ethyl acetate at 0xc2x0 C. was added a 2 mL saturated solution of HCl in ethyl acetate. The reaction mixture was stirred for 30 min. Evaporation of ethyl acetate followed by trituration of the resultant oil gave (0.15 g) of the title compound.
1HNMR (500 MHz, CD3OD): xcex47.40-7.29 (m, 6H), 4.32 (s, 2H), 3.49 (m, 2H), 3.31-3.01 (m, 3H), 2.24 (m, 2H), 1.92 (m, 2H).
Step A: 4-((2-Benzyl-4-iodo)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine
To a mixture of 4-((2-benzyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine (0.15 g, 0.43 mmol). Iodine (0.16 g, 0.65 mmol) and potassium iodide (0.22 g, 1.3 mmol) in 4 mL THF:water (1:1) was added a solution of sodium hydroxide (0.5 mL) and stirred at rt for 30 min. After confirming the completion of reaction by TLC, the reaction was quenched with a saturated solution of sodium thiosulfate and the pH was adjusted to 7-8. The resultant mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried, evaporated and purified by silica column chromatography. Elution with 1% methanol-methylene chloride gave (0.17 g) of the title compound.
1HNMR (500 MHz, CDCl3): xcex47.32-7.22 (m, 5H), 4.13 (br, 2H), 4.06 (s, 2H), 2.74 (m, 3H), 1.47 (s, 3H).
Step B: 4-((2-Benzyl-4-ethenyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine
A mixture of 4-((2-benzyl-4-iodo)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine (0.17 g, 0.36 mmol) from Step A, tri-n-butyl vinyltin (0.17 g, 0.54 mmol) and tetrakistriphenylphosphinyl palladium (0.020 g) in 4 mL toluene was stirred at 100-110xc2x0 C. until the completion of reaction by TLC. Evaporation of the volatiles followed by purification by silica column and elution with 1% methanol-methylene chloride gave (0.061 g) of the title compound.
1HNMR (500 MHz, CDCl3): xcex47.36-7.26 (m, 5H), 6.61-6.55 (m, 1H), 5.10 (m, 2H), 4.33 (br, 2H), 4.13 (s, 2H), 1.47(s, 3H).
Step C: 4-((2-Benzyl-4-ethyl)-1,3-imidazol-2-yl)-1-(t-butoxycarbonyl)piperidine
A mixture of 4-((2-benzyl-4-ethenyl)-1,3-imidaz-5-yl)-1-(t-butoxycarbonyl)piperidine (0.073 g) from Step B in 3.0 mL methanol was hydrogenated over Pd/C (5 mg) at rt. Evaporation of the volatiles followed by purification by preparative silica chromatography and elution with 1% methanol-methylene chloride gave (0.043 g) of the title compound.
1HNMR (500 MHz, CDCl3): xcex47.31-7.20 (m, 5H), 4.19 (br, 2H), 4.01 (s, 2H), 2.74-2.66 9 m, 3H), 2.51 (q, 2H), 1.46(s, 3H), 1.15 (t, 3H).
Step D: 4-((2-Benzyl-4-ethyl)-1,3-imidazol-2-yl)piperidine di-hydrochloride
To 4-((2-benzyl-4-ethyl)-1,3-imidazol-2-yl)-1-(t-butoxycarbonyl)piperidine (0.043 g) from Step C in 1.0 mL ethyl acetate at 0xc2x0 C. was added a 2.0 mL saturated solution of HCl in ethyl acetate. The reaction mixture was stirred for 30 min. Evaporation of ethyl acetate followed by trituration of the resultant oil gave (0.038 g) of the title compound.
Step A: (1-Benzylpiperidin-4-yl)-(cyclohexanon-2-yl)ketone
To a suspension of 1.60 g 60% sodium hydride in 10 mL dry THF was added a solution of 1.963 g (20 mmole) cyclohexanone and 9.893 g (40 mmole) of 1-benzylpiperidine-4-carboxylic acid ethyl ester in 30 mL THF. This mixture was heated to reflux over night. Work-up followed by silica gel FC (15xcx9c50% ethyl acetate in hexanes with 1% triethylamine) provided 4.4 g product containing about 5.7:1 molar ratio of starting 1-benzylpiperidine-4-carboxylic acid ethyl ester and title compound.
ESI-MS 300.3 (M+H), HPLC A: 2.90 and 3.57 min. (for tautomeric forms).
Step B: 4-(2-Ethyl-4,5,6,7-tetrahydro-(2H)-indazol-3-yl)-1-benzylpiperidine
The title compound was prepared from the semi-crude (1-benzylpiperidin-4-yl)-(cyclohexanon-2-yl)ketone from step A and 34% aqueous ethylhydrazine in 4:1 acetonitrile and water at room temperature. This provided 8:1 ratio of isomeric ethyl pyrazoles in favor of the title compound. (Note: Use of ethyl hydrazine oxalate in the presence of DIEA gave about 2:1 ratio of the same isomers.) The 1-benzylpiperidine-4-carboxylic acid ethyl ester present in the starting xcex2-diketone was removed after saponification of the crude product with sodium hydroxide in water ethanol mixture flowed by extractive work-up. The desired ethyl isomer is the higher Rf isomer. It was isolated on silica gel chromatography (60xcx9c100% ethyl acetate in hexanes and 5xcx9c20% methanol in ethyl acetate, both with 1% triethylamine).
1H NMR (500 MHz) xcex47.33xcx9c7.36 (m, 4H), 7.26xcx9c7.30 (m, 1H), 4.07 (q, 7.2 Hz, 2H), 3.57 (s, 2H), 3.00xcx9c3.03 (m, 2H), 2.64xcx9c2.66 (m, 2H), 2.60xcx9c2.63 (m, 2H), 2.57xcx9c2.63 (m, 1H), 1.96xcx9c2.08 (m, 4H), 1.69xcx9c1.81 (m, 6H), 1.39 (t, 7.2 Hz, 3H). The identity of the title compound was confirmed by NOE difference spectroscopy.
Step C: 4-(2-Ethyl-4,5,6,7-tetrahydro-(2H)-indazol-3-yl)piperidine
A mixture of 0.273 g 4-(2-ethyl-4,5,6,7-tetrahydro-(2H)-indazol-3-yl)-1-benzylpiperidine from Step B above, 0.789 g ammonium formate, and 35 mg 20% Pd(OH)2 in 6 mL methanol was heated at 65xc2x0 C. for 1 h. Basic aqueous work-up with ether extraction provided 0.192 g title compound as a colorless solid (97%).
1H NMR (500 MHz) xcex44.08 (q, 7.2 Hz, 2H), 3.19 (br d, 11.9 Hz, 2H), 2.71xcx9c2.77 (m, 1H), 2.68xcx9c2.74 (m, 2H), 2.64xcx9c2.66 (m, 2H), 2.60xcx9c2.62 (m, 2H), 1.82xcx9c1.91 (m, 2H), 1.71xcx9c1.80 (m, 6H), 1.40 (t, 7.2 Hz, 3H). The identity of the title compound was confirmed again by NOE difference spectroscopy.
Step A: 4-(4,5,6,7-Tetrahydro-(2H)-indazol-3-yl)-1-benzyl piperidine, trifluoroacetic acid salt
The title compound was prepared using a procedure similar to that in Procedure 33, Step B with hydrazine instead of ethyl hydrazine. It was further purified on HPLC.
1H NMR (500 MHz, CD3OD) xcex47.47xcx9c7.55 (m, 5H), 4.35 (s, 2H), 3.61 (br d, 12.3 Hz, 2H), 3.13xcx9c3.21 (m, 3H), 2.71xcx9c2.73 (m, 2H), 2.56xcx9c2.58 (m, 2H), 2.17 (br d, 13.3 Hz, 2H), 2.04xcx9c2.12 (m, 2H), 1.79xcx9c1.89 (m, 4H). ESI-MS 296.3 (M+H), HPLC A: 2.33 min.
Step B: 4-(4,5,6,7-Tetrahydro-(2H)-indazol-3-yl)piperidine
The title compound was prepared using a procedure similar to that in Procedure 33, Step C as a white solid.
1H NMR (500 MHz) xcex43.20 (br d, 12.4 Hz, 2H), 2.72xcx9c2.797 (m, 3H), 2.64xcx9c2.66 (m, 2H), 2.49xcx9c2.52 (m, 2H), 1.87xcx9c1.90 (m, 2H), 1.70xcx9c1.84 (m, 6H). ESI-MS 206.2 (M+H), HPLC A: 0.80 min.
3,3-Difluoro-3-(2-pyridyl)propyl)piperidine
Step A: Ethyl oxo(2-pyridyl)acetate
A solution of n-butyl lithium (100 mL, 1.6 M, 160 mmol) in hexanes was added over 2 min. to a stirred solution of 2-bromopyridine (15.0 mL, 24.9 g, 157 mmol) in 500 mL of ether cooled in a dry ice/isopropanol bath, causing a temporary rise in temperature to xe2x88x9247xc2x0 C. After 25 min., the solution was transferred rapidly to a stirred 0xc2x0 C. solution of diethyl oxalate (75 mL, 81 g, 550 mmol) in 1000 mL of ether. After 2 h at 0xc2x0 C., the mixture was washed with saturated aq. sodium bicarbonate (900 mL), water (900 mL), and saturated aq. brine (450 mL). The organic layer was dried (magnesium sulfate), filtered, and evaporated. Distillation gave the title compound as 11.68 g of yellow liquid, B.p. 96-108xc2x0 C. (0.3 mm Hg pressure). For the title compound:
1H NMR (500 MHz, CDCl3) xcex48.78 (d, J=5, 1H), 8.13 (d, J=8, 1H), 7.93 (td, J=8, 2, 1H), 7.56 (ddd, J=8, 5, 1, 1H), 4.51 (q, J=7, 2H), 1.44 (t, J=7, 3H).
Step B: Ethyl difluoro(2-pyridyl)acetate
Ethyl oxo(2-pyridyl)acetate (11.59 g, 64.7 mmol, from Procedure 35, Step A) was added to a flask containing (diethylamino)sulfur trifluoride (18.0 mL, 22.0 g, 136 mmol) and the solution was heated to 45xc2x0 C. overnight. An additional portion of (diethylamino)sulfur trifluoride (24.9 g, 154 mmol) was added and the solution was heated to 55xc2x0 C. for 2 days. After cooling to rt, the solution was added carefully to a stirred mixture of ethyl acetate (600 mL), ice (500 g), water (500 mL), and sodium bicarbonate (100 g). After the resulting reaction had subsided, the layers were separated and the organic layer was washed with 250 mL each of saturated aq. sodium bicarbonate, water, and saturated aq. brine. The organic layer was dried (sodium sulfate), decanted, and evaporated. Distillation gave 8.45 g of yellow liquid, B.p. 50-63xc2x0 C. (0.1 mm Hg), containing a residual impurity. Further purification by flash column chromatography on silica gel, eluting with 80:20 v/v to 75:25 v/v hexanes/ethyl acetate, gave the title compound as 6.54 g of yellow oil. For the title compound:
1H NMR (500 MHz, CDCl3) xcex48.68 (d, J=5, 1H), 7.88 (td, J=8, 2, 1H), 7.76 (d, J=8, 1H), 7.44 (dd, J=8, 5, 1H), 4.40 (q, J=7, 2H), 1.35 (t, J=7, 3H).
Step C: 1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)prop-1-en-1-yl)piperidine
Ethyl difluoro(2-pyridyl)acetate (1.00 g, 4.97 mmol, from Procedure 35, Step B) was dissolved in CH3OH (15 mL) in a 3-neck round bottom flask fitted with a mechanical stirrer, and the resulting solution was cooled in a dry ice/isopropanol bath. Sodium borohydride (114 mg, 3.0 mmol) was added in 2 portions 15 min. apart. After an additional 55 min., the cold reaction was quenched by the addition of saturated aq. ammonium chloride (6.5 mL) over 12 min. After 10 min., the cooling bath was removed and the mixture was stirred for 35 min. before being diluted with saturated aq. brine (100 mL) and extracted with ethyl acetate (4xc3x9775 mL). The combined organic layers were dried (sodium sulfate), decanted, and evaporated to give 1.02 g of crude 2,2-difluoro-2-(2-pyridyl)-1-methoxyethanol as an amber oil.
A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (5.29 g, 9.00 mmol, from Procedure 17, Step C) in THF (70 mL) was stirred at rt for 40 min. A toluene solution of potassium bis(trimethylsilyl)amide (18 mL, 0.5 M, 9.0 mmol) was added, giving an orange suspension. After 40 min., crude 2,2-difluoro-2-(2-pyridyl)-1-methoxyethanol (940 mg, 4.97 mmol) was added in THF (20 mL). After an additional 50 min., the mixture was quenched by the addition of saturated aq. NH4Cl (10 mL). The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), and the aqueous layer was extracted with ethyl acetate (3xc3x97100 mL). The organic layers were washed in succession with saturated aq. brine (100 mL), dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 90:10 v/v to 80:20 v/v hexanes/ethyl acetate, gave 1.18 mg of the title compound (approximately 95:5 cis/trans mixture) as an oil which solidified upon standing. For the title compound:
1H NMR (500 MHz, CDCl3) xcex48.68 (d, J=5, 1H), 7.84 (td, J=8, 2, 1H), 7.70 (d, J=8, 1H), 739 (dd, J=8,5, 1H), 5.93 (td, J=14, 11, 1H), 5.70 (ddt, J=11, 10,2, 1H), 4.17-3.99 (bs, 2H), 2.80-2.62 (m, 3H), 1.58 (d, J=12, 2H), 1.46 (s, 9H), 1.26 (qd, J=12, 4, 2H).
ESI-MS 339 (M+H); HPLC A: 4.28 min.
Step D: 1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)propyl)piperidine
Potassium azodicarboxylate (246 mg, 1.27 mmol) was added to a stirred solution of 1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)prop-1-enyl)piperidine (143 mg, 0.42 mmol, from Procedure 35, Step C) in methanol (1.4 mL) at rt. A solution (0.58 mL) of 75:25 v/v CH3OH/AcOH was added in three portions at 30-min. intervals. After two h, an additional portion of potassium azodicarboxylate (246 mg, 1.27 mmol) was added, followed by a solution (0.58 mL) of 75:25 v/v CH3OH/AcOH added in three portions at 30-min. intervals. After another two h, a third portion of potassium azodicarboxylate (246 mg, 1.27 mmol) was added, followed by a solution (0.58 mL) of 75:25 v/v CH3OH/AcOH added in the same manner as before. After stirring overnight, the mixture was diluted with ethyl acetate (50 mL) and washed with saturated aq. sodium bicarbonate (30 mL) followed by saturated aq. brine (30 mL). The organic layer was dried (sodium sulfate), decanted, and evaporated to give the crude product containing approximately 30% starting olefin. This material was combined with crude product similarly obtained from 1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)prop-1-enyl)piperidine (20 mg, 0.059 mmol) and purified by preparative HPLC on a 20xc3x97250 mm Chiracel OD column, eluting with 98:2 v/v hexanes/isopropanol, to give 105 mg of the title compound:
1H NMR (500 MHz, CDCl3) xcex48.68 (d, J=5, 1H), 7.82 (td, J=8, 2, 1H), 7.64 (d, J=8, 1H), 7.38 (dd, J=8, 5, 1H), 4.17-4.00 (bs, 2H), 2.75-2.62 (m, 2H), 2.42-2.30 (m, 2H), 1.67 (d, J=12, 2H), 1.46 (s. 9H), 1.45-1.38 (m, 3H), 1.15-1.04 (m, 2H).
ESI-MS 241 (M+H-100); HP-LC A: 4.36 min.
Step E: 4-(3,3-Difluoro-3-(2-pyridyl)propyl)piperdine
The title compound was prepared using procedures analogous to those described in Procedure 17, Step H,substituting 1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)propyl)piperidine (from Procedure 35, Step D) for 1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)propyl)piperidine. For the title compound:
1H NMR (500 MHz, CD3OD) xcex48.62 (d, J=5, 1H), 7.95 (td, J=8, 2, 1H), 7.68 (d, J=8, 1H), 7.50 (dd, J=8, 5, 1H), 2.99 (d, J=12, 2H), 2.53 (td, J=12, 3, 2H), 2.37-2.26 (m, 2H), 1.67 (d, J=12, 2H), 1.42-1.28 (m, 3H), 1.08 (dq, J=12, 4, 2H); ESI-MS 241 (M+H); HPLC A: 2.21 min.
Step A: 3-Bromo-6-methylpyridazine
A solution (3.0 mL) containing 30% HBr in acetic acid was added to 3-(trifluoromethanesulfonyloxy)-6-methylpyridazine (prepared as described by M. Rohr, et al., Heterocycles, 1996, 43, 1459-64) and the mixture was heated in a 100xc2x0 C. oil bath for 2.5 h. The mixture was cooled in an ice bath, adjusted to pHxe2x89xa79 (as determined using pH paper) by the careful addition of 20% aqueous NaOH, and extracted with ether (3xc3x9720 mL). The organic layers were dried (sodium sulfate), decanted, and evaporated to give title compound as 359 mg of pale tan crystals. For the title compound:
1H NMR (500 MHz, CDCl3) xcex47.56 (d, J=9, 1H), 7.22 (d, J=9, 1H), 2.70 (s, 3H).
Step B: Ethyl difluoro(6-methylpyridazin-3-yl)acetate
This procedure is derived from the general method of T. Taguchi, et al. (Tetrahedron Lett., 1986, 27, 6103-6106). Ethyl difluoroiodoacetate (0.355 mL, 651 mg, 2.60 mmol) was added to a rapidly stirred suspension of copper powder (333 mg, 5.24 mmol) in DMSO (6.5 mL) at rt. After 50 min., 3-bromo-6-methylpyridazine (300 mg, 1.73 mmol) was added in DMSO (1.0 mL). After 20 h, the mixture was transferred to a separatory funnel containing water (25 mL) and saturated aq. NH4Cl (25 mL), and extracted with ethyl acetate (2xc3x9750 mL). The organic extracts were washed with saturated aq. brine, dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 70:30 v/v hexanes/ethyl acetate, gave 363 mg of the title compound as an amber liquid. For the title compound:
1H NMR (500 MHz, CDCl3) xcex47.79 (d, J=9, 1H), 7.53 (d, J=9, 1H), 4.43 (q, J=7, 2H), 2.82 (s, 3H), 1.38 (t, J=7, 3H).
Steps C-E: 4-(3,3-Difluoro-3-(6-methylpyridazin-3-yl)propyl)piperidine
The title compound was prepared using procedures analogous to those described in Procedure 35, Steps C-E, substituting ethyl difluoro(6-methylpyridazin-3-yl)acetate (from Procedure 36 Step B) for ethyl difluoro(2-pyridyl)acetate in Step C. For the title compound:
1H NMR (500 MHz, CD3OD) xcex47.86 (d, J=9, 1H), 7.74 (d, J=9, 1H), 2.99 (dm, J=12, 2H), 2.74 (s, 3H), 2.54 (td, J=12, 3, 2H), 2.51-2.40 (m, 2H), 1.69 (bd, J=12, 2H), 1.47-1.34 (m, 3H), 1.10 (qd, J=12, 4, 2H).
The title compound was prepared using procedures analogous to those described in Procedure 36, substituting 2-bromo-5-(trifluoromethyl)pyridine for 3-bromo-6-methylpyridazine in Step B. For the title compound:
1H NMR (500 MHz, CD3OD) xcex48.96 (s, 1H), 8.28 (dd, J=8, 2, 1H), 7.88 (d, J=8, 1H), 2.99 (bd, J=12, 2H), 2.53 (td, J=12, 2, 2H), 2.43-2.31 (m, 2H), 1.68 (bd, J=13, 2H), 1.44-1.28 (m, 3H), 1.09 (qd, J=12, 3, 2H); ESI-MS 309 (M+H); HPLC A: 2.32 min.
Step A: Dimethyl (2-oxo-2-(3-pyridyl)ethyl)phosphonate
A solution of n-butyl lithium in hexanes (9.0 mL, 1.6 M, 14 mmol) was added over 10 min. to a solution of dimethyl methylphosphonate (1.50 mL, 1.72 g, 13.8 mmol) in THF (60 mL) cooled in a dry ice/isopropanol bath. After 30 min., a solution of methyl nicotinate (757 mg, 5.52 mmol) in THF (6 mL) was added over 2 min. The solution was stirred in the cooling bath for 45 min. before being allowed to warm to 0xc2x0 C. over 1 h. The reaction was quenched with saturated aq. NH4Cl (50 mL) and then partitioned between saturated aq. brine (50 mL) and methylene chloride (200 mL). The aq. layer was extracted with methylene chloride (2xc3x97100 mL). The combined organic layers were dried (sodium sulfate) decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with ethyl acetate followed by 97:3 v/v methylene chloride/CH3OH, gave material containing some residual impurity. Further purification by flash column chromatography on silica gel, eluting with 50:50:5 v/v/v to 50:50:10 v/v/v toluene/ethyl acetate/CH3OH gave 1.15 g of the title compound. For the title compound: 1H NMR (500 MHz, CDCl3) xcex49.26-9.20 (bs, 1H), 8.83 (d, J=4, 1H), 8.34 (dt, J=8, 2, 1H), 7.70 (dd, J=8, 4, 1H), 3.82 (d, J=11, 6H), 3.67 (d, J=24, 2H).
Step B: 1-(t-Butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)prop-1-enyl)piperidine
1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (750 mg, 1.77 mmol) was added to a solution of 1-(t-butoxycarbonyl)-4-(hydroxymethyl)piperidine (339 mg, 1.57 mmol, from Procedure 17, Step A) in methylene chloride (10 mL) and the mixture was stirred at rt. After 45 min., and additional portion of 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (150 mg, 0.35 mmol) was added. After an additional 30 min., ether (30 mL) and 1.3 N NaOH (10 mL) were added and stirring was continued for 20 min. The mixture was transferred to a separatory funnel with additional ether (30 mL) and 1.3 N NaOH (15 mL). The organic layer was separated, washed with water (20 mL), dried (sodium sulfate), decanted, and evaporated to give 291 mg of 1-(t-butoxycarbonyl)-4-piperidinecarboxaldehyde as a colorless oil.
A solution of dimethyl (2-oxo-2-(3-pyridyl)ethyl)phosphonate (150 mg, 0.65 mmol, from Procedure 38, Step A) in THF (1.8 mL) was added to a stirred suspension of sodium hydride (60% oil dispersion, 15 mg of sodium hydride, 0.63 mmol) in THF (3.0 mL). The resulting suspension was warmed in a 45xc2x0 C. oil bath for 30 min. After the mixture had cooled to rt, 1-(t-butoxycarbonyl)-4-piperidinecarboxaldehyde (112 mg, 0.53 mmol) was added in THF (1.5 mL). After stirring overnight at rt, the mixture was diluted with ether (20 mL) and washed with 2.5 N NaOH (20 mL) followed by saturated aq. brine (20 mL). The aq. layers were extracted in succession with ether (20 mL), and the combined organic layers were dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 80:20 v/v to 60:40 v/v hexanes/ethyl acetate, gave 135 mg of the title compound (trans isomer) as a yellow syrup. For the title compound: 1H NMR (500 MHz, CDCl3) xcex49.17-9.13 (bs, 1H), 8.81 (bd, J=4, 1H), 8.27 (d, J=8, 1H), 7.49 (dd, J=8, 4, 1H), 7.07 (dd, J=15, 7, 1H), 6.85 (dd, J=15, 1, 1H), 4.25-4.13 (bs, 2H), 2.87-2.78 (m, 2H), 2.51-2.41 (m, 1H), 1.83 (d, J=12, 2H), 1.49 (s, 9H), 1.45 (qd, J=12, 4, 2H). ESI-MS 261 (M+H-56), 217 (M+H-100); HPLC A: 1.73 min.
Step C: 1-(t-Butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)propyl)piperidine
1-(t-Butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)prop-1-enyl)piperidine (940 mg, 2.97 mmol, from Procedure 38, Step B) was hydrogenated using 5% Pd/C in 95% ethanol at atmospheric pressure. Purification by flash column chromatography on silica gel, eluting with 90:10 v/v to 50:50 v/v hexanes/ethyl acetate gave 884 mg of the title compound as a colorless syrup. For the title compound:
1H NMR (500 MHz, CDCl3) xcex49.23-9.15 (bs, 1H), 8.81 (bd, J=4, 1H), 8.28 (dt, J=8, 1, 1H), 7.48 (dd, J=8, 4, 1H), 4.19-4.04 (bs, 2H), 3.04 (t, J=8, 2H), 2.70 (bt, J=11, 2H), 1.78-1.70 (m, 4H), 1.56-1.45 (m, 1H), 1.47 (s, 9H), 1.17 (qd, J=12, 4, 2H). ESI-MS 263 (M+H-56), 219 (M+H-100); HPLC A: 1.78 min.
Step D: 1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(3-pyridyl)propyl)piperidine
A solution of 1-(t-butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)propyl)piperidine (810 mg, 2.54 mmol, from Procedure 38, Step C) in (diethylamino)sulfur trifluoride (3.30 mL, 3.66 g, 23 mmol) was stirred in a teflon tube at 40xc2x0 C. for 2 days. The reaction was diluted with methylene chloride (20 mL) and the resulting solution was added in portions to a stirred mixture of water (150 mL), ice (150 g) and sodium bicarbonate (29.3 g). After the resulting reaction had subsided, the mixture was extracted with ethyl acetate (2xc3x97200 mL). The organic layers were washed in succession with saturated aq. brine (100 ML), dried (sodium sulfate), decanted, and evaporated. Flash column chromatography on silica gel, eluting with 80:20 v/v to 50:50 v/v toluene/ether, gave material containing some residual impurity. Further purification by preparative BPLC on a 20xc3x97250 mm Chiracel OD column, eluting with 80:20 v/v hexanes/isopropanol, gave 395 mg of the title compound:
1H NMR (500 MHz, CD3OD) xcex48.69 (s, 1H), 8.64 (d, J=5, 1H), 7.97 (d, J=8, 1H), 7.54 (dd, J=8, 5, 1H), 4.04 (d, J=13, 2H), 2.78-2.62 (bs, 2H), 2.31-2.20 (m, 2H), 1.68 (d, J=12, 2H), 1.50-1.40 (m, 1H), 1.43 (s, 9H), 1.40-1.34 (m, 2H), 1.02 (qd, J=12, 4, 2H). ESI-MS 285 (M+H-56), 241 (M+H-100); HPLC A: 2.10 min.
Step E: 4-(3,3-Difluoro-3-(3-pyridyl)propyl)piperidine
The title compound was prepared using procedures analogous to those described in Procedure 17, Step H,substituting 1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(3-pyridyl)propyl)piperidine (from Procedure 38, Step D) for 1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)propyl)piperidine. For the title compound:
1H NMR (500 MHz, CD3OD) xcex48.68 (s, 1H), 8.64 (d, J=4, 1H), 7.97 (d, J=8, 1H), 7.54 (dd, J=8, 4, 1H), 2.98 (bd, J=12, 2H), 2.52 (td, J=12, 3, 2H), 2.30-2.18 (m, 2H), 1.66 (bd, J=13, 2H), 1.44-1.30 (m, 3H), 1.08 (qd, J=12, 3, 2H); ESI-MS 241 (M+H).
The title compound was prepared using procedures analogous to those described in Procedure 38, substituting ethyl 1-methyl-4-pyrazolecarboxylate, obtained by methylation of ethyl 4-pyrazolecarboxylate with iodomethane and K2CO3 in CH3CN at rt, for methyl nicotinate in Step A. For the title compound:
1H NMR (500 MHz, CD3OD) xcex47.78 (s, 1H), 7.54 (s, 1H), 3.89 (s, 3H), 3.00 (dt, J=12, 3, 2H), 2.55 (td, J=12, 3, 2H), 2.22-2.10 (m, 2H), 1.69 (bd, J=12, 2H), 1.45-1.34 (m, 3H), 1.10 (qd, J=12, 4, 2H). ESI-MS 244 (M+H, 60%), 224 (M-19, 100%); HPLC A: 0.98 min.
The title compound was prepared from 350 mg of 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)piperidine (from Procedure, Step C) and 162 mg of 2-amino-4-chloropyridine (prepared using procedures analogous to those described by R. J. Sundberg et al, Org. Preparations and Procedures Int. 1997, 29, (1), 117-122) in 10 mL ethanol using a procedure analogous to that described in Procedure 27, Step A-B to provide 240 mg of the BOC intermediate as a solid prior to the final de-BOC to give the title TFA salt.
The title compound was prepared according to the general procedures of Procedure 27 and 28, employing 2-amino-4-n-propylpyridine (prepared using a procedure analogous to that described in Procedure 28, Step A) in place of 2-aminopyridine in Procedure 27, Step A.
The title compound was prepared from 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)piperidine (from Procedure 23, Step B) and 2-amino-5-fluoropyridine (prepared using procedures analogous to those described by D. C. Baker et al, Synthesis. 1989, 905) using a procedures similar to that described in Procedure 27, Step A-C.
For the BOC intermediate: 1H NMR (500 MHz, CDCl3): xcex41.51 (s, 9H), 1.60-1.80 (m, 2H), 2.07 (br d, 2H), 2.85-3.00 (m, 3H), 4.20-4.40 (br, 2H), 7.11 (m, 1H), 7.47 (s, 3H), 7.60(m, 1H), 7.89 (m, 1H).
The title compound was prepared using procedures analogous to those described in Procedure 27, Step A-C, except 2-amino-5-fluoro-4-methylpyridine (prepared using procedures analogous to those described by D. C. Baker et al, Synthesis. 1989, 905) was employed in place of 2-amino-5-fluoropyridine in Step A.
Step A: 2-Ethylindazole
To a solution of indazole (6.2 g, 52.5 mmol) in DMF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 3.0 g, 75.0 mmol) at 0xc2x0 C.
After stirring at 0xc2x0 C. for 20 min., ethyl iodide (5 mL, 62.5 mmol) was added dropwise at 0xc2x0 C. The mixture was stirred at rt for 1 h, and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3xc3x97). The combined organic phases were washed with brine, and dried over anhydrous magnesium sulfate. TLC indicated that a 2:1 mixture of two isomers was formed. The mixture was purified by flash chromatography (hexanes:ethyl acetate=4:1, then 1:1) to give 2.34 g of the title compound as a viscous oil (slow moving isomer).
Step B: 2-Ethyl-3-bromoindazole
To a solution of 2-ethylindazole (2.32 g, 15.87 mmol) in ethanol (20 mL) was added bromine (2.54 g, 15.87 mmol) in ethanol (1 mL)/water (1 mL) at 0xc2x0 C. After stirring at 0xc2x0 C. for 10 min. and at rt for 1 h, the reaction was quenched with aq. sodium bicarbonate. The mixture was partitioned between ethyl acetate and aq. sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3xc3x97). The combined organic phase was washed with brine, and dried over anhydrous magnesium sulfate. Purification by flash chromatography (hexanes: ethyl acetate =1:1, then 100% ethyl acetate) gave 2.34 g of the title compound as a viscous oil.
Step C: 1-(t-Butoxycarbonyl)-4-hydroxy-4-(2-ethyl-indazol-3-yl)piperidine
To a solution of 2-ethyl-3-bromoindazole (3.4 g, 15.18 mmol) in THF (30 mL) was added t-BuLi (1.7 M in pentane, 10.72 mL, 18.22 mmol) dropwise at xe2x88x9278xc2x0 C. After stirring at xe2x88x9278xc2x0 C. for 20 min., was added tert-butyl 4-oxo-1-piperidinecarboxylate (3.03 g, 15.18 mmol) in THF (10 mL) dropwise at xe2x88x9278xc2x0 C. The mixture was stirred at xe2x88x9278xc2x0 C. for 10 min. and at rt for 18 h. After the reaction was quenched with aq. NH4Cl, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3xc3x97). The combined organic phases were washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by purification by flash chromatography (hexanes ethyl acetate=4:1, then 1:1) to give 1.18 g of the title compound as a foamy solid.
Step D: 1-(t-Butoxycarbonyl)-4-(2-ethyl-indazol-3-yl)-[1,2,3,6]tetrahydropyridine
To a solution of 1-(t-butoxycarbonyl)-4-hydroxy-4-(2-ethyl-indazol-3-yl)piperidine (651 mg, 1.89 mmol) in toluene (5 mL) was added (methoxycarbonylsulfamoyl)-triethylammonium hydroxide inner salt (540 mg, 2.27 mmol). After heating up to xcx9c70xc2x0 C. for 10 min., was added additional 5 mL of toluene. The mixture was stirred at 70xc2x0 C. for additional 2 h. The mixture was partitioned between ethyl acetate and aq. sodium bicarbonate. Aqueous layer was extracted with ethyl acetate (3xc3x97). The combined organic phases were washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by purification by flash chromatography (hexanes:ethyl acetate=4:1, then 1:1) gave 514 mg of the title compound as a viscous oil.
Step E: 1-(t-Butoxycarbonyl)-4-(2-ethyl-[5,6,7,8]tetrahydroindazol-3-yl)piperidine
A solution of 1-(t-butoxycarbonyl)-4-(2-ethyl-indazol-3-yl)-[1,2,3,6]tetrahydropyridine (500 mg, 1.53 mmol) in methanol (5 mL) was hydrogenated using Pd(OH)2 (100 mg) under atmospheric H2 for 4.5 h. After the addition of Platinum (IV) oxide (100 mg) hydrogenation was continued for additional 4 h. The mixture was filtered through celite and concentrated to give the title compound (461 mg) as a viscous oil. ESI-MS 333 (M+1); HPLC A: 2.45 min.
Step F: 1-(t-Butoxycarbonyl)-4-(2-ethylindazol-3-yl)piperidine
To a solution of 1-(t-butoxycarbonyl)-4-(2-ethyl-[5,6,7,8]tetrahydroindazol-3-yl)piperidine (80 mg, 0.24 mmol) in toluene (3 mL) was added DDQ (115 mg, 0.51 mmol) at rt. After refluxing for 4 h, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3xc3x97). The combined organic phases were washed with brine, and dried over anhydrous magnesium sulfate. Concentration gave 25 mg of the title compound as a viscous oil.
ESI-MS 274 (M+1-t-Bu); HPLC A: 3.09 min.
Step G: 4-(2-Ethylindazol-3-yl)piperidine, TFA salt
Using essentially the same method as Procedure 27, Step B, the title compound was obtained as the TFA salt
Step A: 1-(t-Butoxycarbonyl)-4-(N-methyl-N-methoxycarboxamido)piperidine
A solution of 1-(t-butoxycarbonyl)isonipecotic acid (13.74 g, 0.06 mol), TEA (14.7 mL, 0.105 mol), 4-DMAP (1.83 g, 0.015 mol), N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimidexc3x97HCl (11.50 g, 0.06 mol) and O,N-dimethylhydroxylaminexc3x97HCl (6.27 g, 0.09 mol) in methylene chloride (250 mL) was stirred at rt for 60 h. The mixture was partitioned between 1 L of ether and 500 mL of water and the layers were separated. The organic layer was washed with 500 mL of 1.0 N HCl, 500 mL of 1.0 N NaOH, 500 mL of sat""d sodium chloride, dried over magnesium sulfate and concentrated to afford 14.34 g (88%) of the title compound:
1H NMR (500 MHz) xcex41.46 (s, 9H), 1.65-1.80 (4H), 2.76-2.86 (3H), 3.19 (s, 3H), 3.71 (s, 3H), 4.15 (2H).
Step B: 1-(t-Butoxycarbonyl)-4-formylpiperidine
A solution of 1-(t-butoxycarbonyl)-4-(N-methyl-N-methoxycarboxamido)piperidine (4.80 g, 17.6 mmol) (from Step A) in methylene chloride (100 mL) at xe2x88x9278xc2x0 C. was treated with 1.0 M DIBALH solution in methylene chloride (25 mL) and stirred cold for 30 min. The reaction was quenched with 1.0 N HCl (250 mL) and warmed to rt. The quenched mixture was extracted with 300 mL of ether; the extract was washed with 150 mL of 1.0 N NaOH, 150 mL of sat""d sodium chloride, dried over magnesium sulfate and concentrated. Flash chromatography on 125 g of silica gel using 1:1 v/v hexanes/ether as the eluant afforded 3.60 g (95%) of the title compound:
1H NMR (500 MHz) xcex41.46 (s, 9H), 1.52-1.59 (m, 2H), 1.85-1.91 (m, 2H), 2.38-2.43 (m, 1H), 2.93 (app t, J=11.0, 2H), 3.95-4.05 (m, 2H), 9.66 (s, 1H).
Step C: 1-(t-Butoxycarbonyl)-4-(1-(RS)-hydroxy-2-(RS)-methyl-3-oxopent-1-yl)piperidine
A solution of diisopropylamine (0.63 mL, 4.5 mmol) in THF (16 mL) at 0xc2x0 C. was treated with 1.6 M n-butyllithium in sol""n in hexanes (2.8 mL). The resulting solution was stirred at 0xc2x0 C. for 10 min, then cooled to xe2x88x9278xc2x0 C. 3-Pentanone (0.41 mL, 4.1 mmol) was added and the resulting mixture was stirred cold for 1 h. A solution of 1-(t-butoxycarbonyl)4-formylpiperidine (435 mg, 2.05 mmol) (from Step B) in THF (3 mL) was then added. After 15 min, the reaction was quenched with sat""d ammonium chloride (25 mL) and extracted with ether (100 mL). The extract was dried over magnesium sulfate and concentrated. MPLC (Biotage) on a 40S silica cartridge using 4:1 v/v, then 3:2 v/v hexanes/ethyl acetate as the eluent afforded 517 mg (85%) of the title compound.
Step D: 1-(t-Butoxycarbonyl)-4-(1,3-dioxo-2-(RS)-methylpent-1-yl)piperidine
A solution of oxalyl chloride (0.34 mL, 3.9 mmol) in methylene chloride (12 mL) at xe2x88x9278xc2x0 C. was treated with DMSO (0.43 mL, 6.0 mmol) and the resulting mixture was stirred cold for 10 min. A solution of 1-(t-butoxycarbonyl)-4-(1-(RS)-hydroxy-2-(RS)-methyl-3-oxopent-1-yl)piperidine (514 mg, 1.7 mmol) (from Step C) was added and the resulting solution was stirred cold for 1 h. N,N-Diisopropylethylamine (2.4 mL, 13.7 mmol) was added and the resulting mixture was warmed to 0xc2x0 C. The reaction was quenched with 1.0 N HCl (25 mL) and extracted with ether (100 mL). The extract was dried over magnesium sulfate and concentrated. MPLC (Biotage) on a 40S silica cartridge using 2:1 v/v hexanes/ethyl acetate as the eluent afforded 435 mg (85%) of the title compound.
Step E: 1-(t-Butoxycarbonyl)-4-(1,3-diethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine
A solution of 1-(t-butoxycarbonyl)-4-(1,3-dioxo-2-(RS)-methylpent-1-yl)piperidine (435 mg, 1.5 mmol) (from Step D) in 2:1 v/v acetonitrile/water (12 mL) was treated with ethylhydrazine (34% sol""n in water, 0.28 mL, 1.6 mmol) and the resulting mixture was stirred at rt for 20 h. The reaction mixture was partitioned between 75 mL of ether and 25 mL of sat""d sodium chloride and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated. MPLC (Biotage) on a 40S silica cartridge using 4:1 v/v, then 1:1 v/v hexanes/ethyl acetate as the eluent afforded 348 mg (74%) of the title compound:
1H NMR (500 MHz) xcex41.21 (t, J=7.5, 3H), 1.36 (t, J=7.5, 3H), 1.49 (s, 9H), 1.68-1.72 (m, 2H), 1.86-1.91 (m, 2H), 2.54 (q, J=1.5, 2H), 2.72-2.79 (3H), 4.08 (qd, J=, 2H), 4.20-4.30 (m, 2H).
Step F: 4-(1,3-Diethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine di-HCl salt
A solution of 1-(t-butoxycarbonyl)-4-(1,3-diethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine (348 mg) (from Step E) in 2.5 N HCl in methanol was stirred at rt for 16 h. The solution was concentrated and the resulting solid was suspended in ethyl acetate, filtered and dried to afford 293 mg (92%) of the title compound.
Using essentially the same methods as described in Procedure 45 and substituting the appropriate starting material and/or hydrazine reagent, a variety of other 4-(1,3,4-trialkyl)-(1H)-pyrazol-5-yl)piperidines can be prepared, usually as the di-hydrochloride salts, and utilized in the following Examples as required.
Using essentially the same methods as described in Procedures 1 and 2 and substituting the appropriate starting material and/or hydrazine reagent, the following representative 4-(3-(substituted)-1-(H or alkyl)-(1H)-pyrazol-5-yl)piperidines can be prepared, usually as the di-hydrochloride salts, and utilized in the following Examples as required.
4-(3-(Benzyl)-1-(methyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(Benzyl)-1-(n-propyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(Benzyl)-1-(isopropyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(2-Fluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Fluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Fluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Fluorobenzyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Fluorobenzyl)-1-(methyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Fluorobenzyl)-1-(n-propyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3,4-Difluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3,4-Difluorobenzyl)-1-(methyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3,4-Difluorobenzyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3,5-Difluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(2,4-Difluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Chlorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Chlorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3,4-Dichlorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Cyanobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Cyanobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Methylsulfonylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Methylsulfonylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Methoxybenzyl)-1-(methyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Methoxybenzyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Ethoxybenzyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Isopropoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Isopropoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Cyclopropoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Butoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-t-Butoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Cyclobutoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Difluoromethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Trifluoromethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Trifluoroethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3,4-Methylenedioxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl) piperidine
4-(3-(3,4-Dimethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3,4-Diethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Fluoro-4-methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Fluoro-3-methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Fluoro-4-ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Fluoro-3-ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Cyano-3-methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Cyano-3-methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Cyano-4-ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Cyano-3-ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(Benzofuran-6-yl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(Benzofuran-5-yl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(2,3-Dihydrobenzofuran-6-yl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Benzyloxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-hydroxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Methylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Methylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Ethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Ethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Ethylbenzyl)-1-(methyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Ethylbenzyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Isopropylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-t-Butylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Trifluoromethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Phenylbenzyl)-1-(ethyl)-(H)-pyrazol-5-yl)piperidine
4-(3-(4-Phenylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Naphthyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(2-Naphthyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Acetylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-(1-Methyl-1-hydroxyethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(3-Trifluoromethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Trifluoromethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(Pyridin-3-yl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(Pyridin-3-yl)-(1H)-pyrazol-5-yl) piperidine
4-(3-(Cyclohexylmethyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(4-Methylcyclohexylmethyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(Cycloheptylmethyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(Pyran-4-ylmethyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine
4-(3-(Thiopyran-4-ylmethyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine, S,S-dioxide
Using essentially the same methods as described in Procedures 22-26 and substituting the appropriate starting material and/or reagent, the following representative 4-(2-(substituted)-4-(H or alkyl)thiazol-5-yl)piperidines can be prepared, usually as the di-hydrochloride salts, and utilized in the following Examples as required.
4-(2-(Benzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(Benzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(Benzyl)thiazol-5-yl)piperidine
4-(2-(2-Fluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(2-Fluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(2-Fluorobenzyl)thiazol-5-yl)piperidine
4-(2-(3-Fluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3-Fluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3-Fluorobenzyl)thiazol-5-yl)piperidine
4-(2-(4-Fluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Fluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Fluorobenzyl)thiazol-5-yl)piperidine
4-(2-(2-Chlorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(2-Chlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(2-Chlorobenzyl)thiazol-5-yl)piperidine
4-(2-(3-Chlorobenzyl)-4-(ethyl)thiazo-5-y)piperidine
4-(2-(3-Chlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3-Chlorobenzyl)thiazol-5-yl)piperidine
4-(2-(4-Chlorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Chlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Chlorobenzyl)thiazol-5-yl)piperidine
4-(2-(3-Cyanobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3-Cyanobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3-Cyanobenzyl)thiazol-5-yl)piperidine
4-(2-(4-Cyanobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Cyanobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Cyanobenzyl)thiazol-5-yl)piperidine
4-(2-(3,4-Difluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3,4-Difluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3,4-Difluorobenzyl)thiazol-5-yl)piperidine
4-(2-(3,5-Difluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3,5-Difluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3,5-Difluorobenzyl)thiazol-5-yl)piperidine
4-(2-(2,4-Difluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(2,4-Difluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(2,4-Difluorobenzyl)thiazol-5-yl)piperidine
4-(2-(3,4-Dichlorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3,4-Dichlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3,4-Dichlorobenzyl)thiazol-5-yl)piperidine
4-(2-(3,5-Dichlorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3,5-Dichlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3,5-Dichlorobenzyl)thiazol-5-yl)piperidine
4-(2-(2,4-Dichlorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(2,4-Dichlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(2,4-Dichlorobenzyl)thiazol-5-yl)piperidine
4-(2-(3-Methylbenzyl)4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3-Methylbenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3-Methylbenzyl)thiazol-5-yl)piperidine
4-(2-(4-Methylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Methylbenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Methylbenzyl)thiazol-5-yl) piperidine
4-(2-(3-Ethylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3-Ethylbenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3-Ethylbenzyl)thiazol-5-yl) piperidine
4-(2-(4-Ethylbenzyl)4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Ethylbenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Ethylbenzyl) thiazol-5-yl) piperidine
4-(2-(4-Isopropylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Isopropylbenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Isopropylbenzyl )thiazol-5-yl)piperidine
4-(2-(4-t-Butylbenzyl)4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-t-Butylbenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-t-Butylbenzyl)thiazol-5-yl)piperidine
4-(2-(3-Trifluoromethylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3-Trifluoromethylbenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3-Trifluoromethylbenzyl)thiazol-5-yl)piperidine
4-(2-(4-Trifluoromethylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Trifluoromethylbenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Trifluoromethylbenzyl)thiazol-5-yl) piperidine
4-(2-(3-Methoxybenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3-Methoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3-Methoxybenzyl)thiazol-5-yl)piperidine
4-(2-(4-Methoxybenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Methoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Methoxybenzyl)thiazol-5-yl)piperidine
4-(2-(3-Ethoxybenzyl)4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3-Ethoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3-Ethoxybenzyl)thiazol-5-yl)piperidine
4-(2-(4-Ethoxybenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Ethoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Ethoxybenzyl)thiazol-5-yl)piperidine
4-(2-(3-Trifluoromethoxybenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(3-Trifluoromethoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(3-Trifluoromethoxybenzyl)thiazol-5-yl)piperidine
4-(2-(4-Trifluoromethoxybenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Trifluoromethoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Trifluoromethoxybenzyl)thiazol-5-yl)piperidine
4-(2-(4-Methylsulfonylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Methylsulfonylbenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Methylsulfonylbenzyl)thiazol-5-yl)piperidine
4-(2-(4-Nitrobenzyl)-4-(ethyl)thiazol-5-yl)piperidine
4-(2-(4-Nitrobenzyl)-4-(methyl)thiazol-5-yl)piperidine
4-(2-(4-Nitrobenzyl)thiazol-5-yl) piperidine
Step A: (1-(t-Butoxycarbonyl)piperidin-4-yl)N-methyl-N-methoxycarboxamide 
A 100 L round-bottomed-flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet was charged with DMF (51 L), N,O-dimethylhydroxyamine hydrochloride (2.62 Kg, 26.55 mol), HOBT (1.2 Kg, 8.85 mol), and N-Boc isonipecotic acid (4.10 Kg, 17.70 mol). The mixture warmed to 18xc2x0 C. as the diisopropylethylamine (4.60 Kg, 6.2 L, 35.41 mol) was added over 15 min. The EDC.HCl (5.09 Kg, 26.55 mol) was added in three portions over 3 h maintaining an internal temperature of 18xc2x0 C. with gentle cooling. The reaction mixture was held at 18xc2x0 C. for 12 h. HPLC analysis shows no remaining 1. The reaction mixture was pumped into an extractor containing 74 L of water at 5xc2x0 C. The resulting solution (39.3 g/L of 2) was extracted with ethyl acetate (4xc3x9737 L).
The organic phases were combined and washed with 1 N HCl (2xc3x977 L), water (5 L), then brine (10 L then 5 L). The final organic phase was 125.4 Kg (d=0.878) with a concentration of 2 at 36.9 g/L (5.27 Kg).
Step B: 1-(t-Butoxycarbonyl)-4-acetylpiperidine 
The ethyl acetate solution of (1-(t-butoxycarbonyl)piperidin-4-yl)-N-methyl-N-methoxycarboxamide from Step A (4.44 Kg, 16.29 mol) was dried over anhydrous sodium sulfate (1.6 Kg). The drying agent was removed by filtration then the solvent was removed in vacuo to provide a clear light yellow oil that was held for 16 h under high vacuum to provide a crystalline solid. The solid was dissolved in THF (55 L) then cooled to xe2x88x9220xc2x0 C. Methyl magnesium chloride (3.12 M in THF, 12.0 L, 37.4 mol) was added over 1.75 h keeping the internal temperature below 0xc2x0 C. The resulting gray suspension was aged at 0xc2x0 C. for 2 h then 25xc2x0 C. for 3 h. An aliquot was drawn and worked up with ethyl acetate, acetic acid and water. The batch was cooled to 9xc2x0 C., then pumped over 15 min into an extractor charged with a solution of 41 L of water and 4.9 L of acetic acid at 5xc2x0 C. Ethyl acetate (52 L) was charged to the extractor, the phases were mixed then the lower aqueous phase (44.3 Kg) was cut away. The organic phase was washed with sat""d aq. sodium bicarbonate (2xc3x97), 7% aq. sodium chloride (2xc3x97) and sat""d aq. sodium chloride. The organic phase (116.2 L, 30.3 g/L of 3) contained 3.52 Kg of the title compound 3 (87.5% yield from 1). The organic phase was dried over anhydrous sodium sulfate (1.5 Kg). The drying agent was removed by filtration, then the solution was batch concentrated to an oil. The compound was diluted with THF and the batch was flushed with 20 L of THF. The residual oil was diluted with THF (5 L).
Step C: 1-(1-(t-Butoxycarbonyl)piperidin-4-phenylbutane-1,3-dione 
A 72 L round-bottomed-flask equipped with a mechanical stirrer, nitrogen inlet, thermocouple and 5 L dropping funnel was placed in a temperature control bath. Under a nitrogen sweep, the flask was charged with the NaH (60% in mineral oil, 1.55 Kg, 38.75 mol) and THF (20 L). The batch warmed from 17xc2x0 C. to 22xc2x0 C. as methanol (0.10 Kg, 130 mL, 3.09 mol) was added over 45 min (hydrogen evolution!!). The solution of 1-(t-butoxycarbonyl)-4-acetylpiperidine from Step B (3.52 Kg, 15.49 mol) was added over 1 h. To the resulting suspension was added a solution of the methyl phenylacetate 2.46 Kg, 17.04 mol) and THF (5 L) over 8 h maintaining a reaction temperature of about 25xc2x0 C. by cooling as needed. The mixture was aged at 23xc2x0 C. for 15 h.
The batch was cooled to 17xc2x0 C. then pumped into a 100 L extractor containing a solution of concentrated HCl (3.3 L) and water (16 L) at xe2x88x926xc2x0 C. (caution, hydrogen evolution!!). The mixture was stirred, allowed to partition then the pH of the aqueous phase was checked (pH=1 to 2). The layers were partitioned and the organic phase was washed with a solution of saturated aqueous sodium bicarbonate (5 L) and brine (1 L) then brine (4 L). MTBE (7.7 L) was added to the extractor along with the acidic first aqueous phase. The mixture was shaken to mix well, allowed to partition then the aqueous was cut away. The sodium bicarbonate phase was added, mixed, allowed to partition then the aqueous was cut away. The brine phase was added to the extractor, the mixture mixed, allowed to partition then the aqueous phase was cut away. The MTBE and THB phases were combined then concentrated to an oil. To the oil was added silica gel 60 (7 Kg) and 5% ethyl acetate/heptanes (10 L) with stirring to provide a slurry. The slurry was poured onto a column containing silica gel 60 (23 Kg) wet with 5% ethyl acetate/heptanes. The column was eluted with 5% etyl acetate/heptanes (200 L) then 20% ethyl acetate/heptanes (200 L) at the rate of 2.2 L/min to obtain the product 4. The rich cut was batch concentrated to provide a slightly yellow slurry that was taken up in DMF (15 L) to provide a clear solution. The batch concentration was continued to remove all residual heptanes and ethyl acetate. To the batch at 18xc2x0 C. was slowly added water (3.5 L) until the mixture became turbid. The batch was seeded and additional water was added to a total of 8.0 L (final solvent mixture was 35% water and 65% DMF). The batch was cooled to 1xc2x0 C. The solids were collected on a frit, washed with 5 L of water then dried under a stream of nitrogen to provide 4 (3.57 Kg, 66.7% from 3, 57.8% from 1).
Step D: 1-(t-Butoxycarbonyl)-4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidine 
A 100 L cylindrical flask with a bottom valve was equipped with a mechanical stirrer, internal heating coil, 5 L dropping funnel, and thermocouple was charged with the acetonitrile (39 L) and 1-(1-(t-butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione 4 (3.00 Kg, 8.68 mol). To the resulting clear light yellow solution was added water (18.6 l). The mixture was warmed to 19xc2x0 C. and the mixture became clear. An ethyl hydrazine solution (35% in water, 1.66 Kg, 1.71 L, 9.55 mol) was added via a dropping funnel over 100 min. The batch temperature after the addition was 20xc2x0 C. The reaction solution was aged for 1 h at 20xc2x0 C. then checked for completion by HPLC. If any 4 remained, additional ethyl hydrazine was added to complete the reaction. At the end of reaction the ratio of products 5:6:7 is 83.6:14.3:2.1 with complete consumption of 4.
The dropping funnel was removed and a Dean Stark trap was fitted to the flask. To the reaction mixture was added heptanes (5 L) and the acetonitrile was removed by azeotropic distillation at 64xc2x0 C. During the distillation, the initial reaction volume was maintaining by periodic addition of heptanes. When the internal temperature reached 72xc2x0 C., the batch was cooled to 60xc2x0 C. and the heavy aqueous phase was cut away. The distillation was resumed until the internal temperature reached 95xc2x0 C. and no water droplets were observed in the distillate. The batch was cooled to 50xc2x0 C., seeded then cooled to 5xc2x0 C. over 16 h. The resulting solids were collected on a frit, rinsed with heptanes (10 L at 5xc2x0 C.), then dried under dry nitrogen to provide 2.58 Kg (80.3% yield) of a crystalline solid that was a 98.67:0.49:0.84 mixture of 5:6:7.
Step E: 4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidine di-HCl salt
1-(t-Butoxycarbonyl)4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-ylpiperidine 5 from Step D (18.5 g, 50 mmol) was added to a solution of HCl (530 mmol) in methanol (300 mL) prepared by the slow addition of acetyl chloride (38 mL, 530 mmol) and aged for 90 min. The reaction was stirred at rt for 16 h and then evaporated to dryness to afford 17.1 g (100%) of the title compound as a hygroscopic white solid.